Novel compounds for the management of aging-related and diabetic vascular complications, process for their preparation, therapeutic and cosmetic uses thereof

ABSTRACT

The invention discloses a new clause of a five membered heterocylic ring compounds of general formula I  
                 
and its pharmaceutically or cosmetically acceptable salts, wherein R1, R2, R3, R4, R5, A, B, X and Y are as defined in the specification. The invention also discloses a process for preparation of these compound and their therapeutic and cosmetic applications particularly in the management of aging related and diabetic vascular complications. The compounds in question act by triple action of an AGE (Advanced Glycation Endproducts) breaker, AGE inhibitor and free radical scavenger which make them most suitable in different therapeutic and cosmetic applications. The invention also discloses pharmaceuticals and cosmetic compositions comprising these compounds and method of treatment of diseases caused by accumulation of AGE and/or free radicals in the body cells.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 10/116,135filed Apr. 5, 2002, which claims benefit from U.S. provisionalApplication No. 60/281,380 filed Apr. 5, 2001; the above-notedapplications incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a new class of compounds of fivemembered heterocyclic ring compounds and to their use in treatment ofdiabetes and related illnesses. More particularly the invention relatesto compounds of this series, methods for their preparation,pharmaceutical composition containing these compounds and their use inthe treatment of complications of diabetes mellitus. The compounds ofthis series exhibit AGE breaking and inhibiting activity, which isessential for the treatment of diabetic and aging-related vascular andneurovascular complications including kidney disease, nerve damage,atherosclerosis, retinopathy, inflammatory disorders, immunologicaldisorders, oxidative stress and dermatological & cosmetic indications.

The invention also extends to the method of reversing the discolorationof teeth resulting from nonenzymatic browning in the oral cavity byadministration of an effective amount of these compounds to reversepre-formed advanced glycosylation crosslinks.

These compounds, also exhibit free radical scavenging activity and henceare useful in the treatment of diseases caused by free radicals besidestheir cosmetic applications

The triple function of a free radical scavenger, AGE breaker and AGEinhibitor of these compounds can be effectively used in cosmeticcompositions which are capable of arresting and reversing the process ofskin aging resulting from an increased accumulation of advancedglycation end-products (AGEs) on the skin proteins and photo damagethrough free radical actions. The invention further relates tocomposition and method for scavenging free-radicals from the body cells.

2. Description of the Related Art

Maillard in 1912 found that reducing sugars, such as glucose and ribosereact with proteins to form brown pigments. Further studies have shownthat this is an irreversible non-enzymatic reaction, which occurs inseveral natural systems including stored foodstuff. Maillard reactionoccurs in two stages, early and advanced. Initially, proteins react withglucose to form stable Amadori products, which subsequently cross-linksto form advanced glycation end products (AGE). In most cases, theformation of AGE also accompanies browning of the proteins and increasein the fluorescence.

In diabetes, where blood glucose level is significantly higher thannormal, the reaction of glucose with several proteins such ashemoglobin, lens crystallin and collagen, gives rise to the formation ofAGE, which in turn, is responsible for the complications associated withdiabetes, such as nephropathy, microangiopathy, endothelial dysfunctionand other organ dysfunctions. In addition, the activity of severalgrowth factors, such as basic fibroblast growth factor, is alsoimpaired. AGE products, unlike normal proteins in tissue, have a slowerrate of turnover and replenishment. It has been reported that AGEproducts may in fact elicit a complex immunological reaction involvingRAGE (Receptor for Advanced Glycation End Products) receptors andactivation of several incompletely defined immunological processes. Ithas been documented that diabetes with evidence of microangiopathy andmacroangiopathy also show evidence of oxidative stress, the mechanism ofwhich has not been elucidated.

In vitro AGE formation can be studied in the laboratory by incubatingreducing sugars, such as ribose or glucose with bovine serum albumin.AGE formation can be detected by increase in the fluorescence orincreased cross reactivity with anti-AGE antibodies. The increase influorescence seems to precede formation of AGE specific antigenicepitopes. This increase in fluorescence is used to monitor the increasedAGE formation in vitro (Brownlee M et al, Science 1986; 232:1629-1632).In addition to the increase in the fluorescence, one of the mostimportant features of in vitro AGE formation is the formation ofantigenic epitopes that are specific to AGE and not to the nativeproteins. Therefore, it is possible to raise antibodies against advancedglycation end products of one protein and use them to detect AGEformation in other proteins. This has served as an important analyticaltool in AGE research.

Due to the clinical significance of AGE formation, many approaches arebeing used to diagnose, prevent, or revert AGE formation in the body.The formation of AGE could be inhibited by reacting with an earlyglycosylation product that results from the original reaction betweenthe target protein and glucose. The inhibition was believed to takeplace as the reaction between the inhibitor and the early glycosylationproduct appeared to interrupt the subsequent reaction of theglycosylated protein with additional protein material to form the crosslinked late stage product. Compounds like aminoguanidine act to inhibitAGE formation by such mechanism.

The formation of AGE on long-lived proteins is also associated withcross-linking of these proteins. The AGE derived protein cross-linkshave been shown to be cleaved by compounds like N-phenacyl thiazoliumbromide (PTB), which reacts with and cleaves covalent, AGE derivedprotein cross links (Vasan et al. Nature 1996; 382: 275-278; U.S. Pat.No. 5,853,703, Date of patent: Dec. 29, 1998). The mechanism of reducingthe AGE content in tissues is expected to take place relatively rapidly,in contrast to aminoguanidine, which acts slowly by its very nature ofmechanism of action.

The compounds which are AGE breaker or AGE inhibitor are of primeimportance in therapeutic applications as mentioned below:

AGE Breakers:

The compounds which can break the accumulated AGE can be used as amedicament in the treatment of diabetic complications and aging-relateddiseases caused by accumulation of AGE.

The compounds which can inhibit accumulation of AGE by breaking AGE, canbe used as a medicament for arresting the aggravation of diseases suchas diabetes and aging related complications caused by accumulation ofAGE.

AGE Inhibitors:

The compounds which can inhibit accumulation of AGE by inhibitingformation of AGE, can be used in a medicament for the diseases such asdiabetes and aging related complications caused by accumulation of AGE.

The unchecked formation of AGE in vivo, such as in diabetics relateddiseases, can lead to severe physiological impairment. For example, indiabetic neuropathy and retinopathy, the functional integrity of thecapillary wall barrier and inner blood retinal barrier, respectively,are defective, as evidenced by the abnormal attachment of theendothelium to the basement membrane. This defect is a directconsequence of the cross-linking of structural proteins by glycation.The etiology of diabetic neurovascular disorders, as well asimmunological disorders, is the formation of AGE. Currently, it isbelieved that inhibiting AGE formation, or the breaking of existing AGE,would be beneficial in a variety of diseases, including nephropathy,neuropathy, arteriosclerosis, and dermatological disorders.

Studies have demonstrated positive effects of agents that break AGE,such as in studies on cardiovascular complications related to aging, acondition which is accelerated in experimental diabetic conditions(Wolffenbuttel et al., 1998).

In another pharmacological approach to controlling levels of AGE intissues, especially in those tissues in which AGE has alreadyaccumulated to levels which are responsible for sub-clinical or clinicalpathology, administration of agents that reverse or break AGE has provensuccessful. As described in U.S. Pat. Nos. 5,656,261 and 5,853,703agents and methods are disclosed which reverse (or cleave or break) AGEformation in vitro and in vivo.

Several successful therapeutic approaches have also been achieved basedupon blocking the accumulation of AGE in vivo. One approach, exemplifiedin U.S. Pat. No. 4,758,583 concerns the inhibition of the formation ofAGE from its precursors, by the administration of agents such asaminoguanidine and related compounds.

As has been shown in the above-cited references, compounds which blockAGE formation, or break AGE, are reasonably correlated to the treatmentof AGE-related disorders, such as diabetic nephropathy, neuropathy,retinopathy, and arteriosclerosis, dermatological disorders,non-enzymatic browning of the oral cavity, endothelial or other organdysfunction and growth impairment.

The correlation between the onset of AGE with various diseases has alsobeen described in various literature as discussed below.

The correlation between the formation of Advanced Glycation End products(AGE) and nephropathy is well established by several researchpublications. Beisswenger (1995) has shown that AGE concentration inhuman diabetic subjects correlates with early manifestation of renaldiseases. Makita et al (1991) has shown that increase in AGE peptidesparallels with the severity of renal dysfunction. The above citationsclearly show that AGE is the principal cause of diabetic nephropathy.Yamauchi (1997) showed that prevention of AGE formation byaminoguanidine inhibits development of diabetic nephropathy.Aminoguanidine administration is also shown to ameliorate thickening ofglomerular basement membrane of diabetic rats (Ellis 1991).Aminoguanidine is also shown to attenuate the rise in albuminuria inexperimental diabetic rats (Soulis-Liparota, 1991).

AGE is also shown to induce expression of vascular endothelial growthfactor in retinal muller cells (Hirata, 1997, Murata, 1997) andtherefore may promote intraocular neovascularization in diabeticretinopathy. Aminoguanidine treatment is shown to retard progression ofdiabetic retinopathy in rat model (Hammes, 1991, Hammes, 1994, Roufail,1998).

Aminoguanidine treatment is also shown to improve nerve conductionvelocity in diabetic rats (Kihara, 1991 Miyauchi, 1996 and Yagihashi,1992).

Bucala (1996) has extensively reviewed various aspects of development ofAtheroscelrosis and stated that accumulation of AGE can trigger a seriesof cellular events, such as cellular oxidative stress, expression ofadhesion molecules, endothelial transmigration of monocytes, etc. andthese events can lead to atherosclerosis. Kirstein (1990) havedemonstrated that (i) in vitro and in vivo-formed AGE proteins arechemotactic for human blood monocytes, (ii) sub-endothelial AGE caninduce monocyte migration across intact endothelium and (iii)interaction of monocyte with AGE containing matrix results intoinduction platelet derived growth factor.

Thus, it can be concluded that AGE, upon interaction with endothelialcells through its receptor RAGE, activate nuclear factor Kappa B andinduce various genes expressing adhesion molecules. AGE-endotheliuminteractions also increase oxidative stress, initiate monocytemigration, block endothelial nitric oxide and stimulate angiogenesis.All these conditions result in conditions such as atherosclerosis.

Other dysfunctions demanding lower tissue AGE burden include,Hypertension, Restenosis, abnormal tissue hindrance in peritonealdialysis, Erectile Dysfunction and Alzheimer disease. Similarly, on theother hand, non-enzymatic cross-linking of structural proteins, such ascollagen, leads to increased stiffness of arteries and reduce arterialcompliance and distensibility. In fact, treatment of AGE-breaker ALT-711is shown to reverse diabetes induced increase of arterial stiffness andimprove arterial compliance (Wolffenbutel 1998). Aronson et al (1996)have reviewed role of AGE in promoting inflammatory cell recruitment andsmooth muscle proliferation and suggested it to be a likely reason forgreater restenosis, abnormal tissue hindrance in peritoneal dialysisrate in diabetic patients.

Seftel (1997) has shown significant elevation of pentosidine in thepenile tissue of diabetic patients as compared to non-diabetic. Theyhave speculated a mechanism for AGE mediated erectile dysfunction viaupregulation of inducible nitric oxide and downregulation of endothelialnitric oxide in penile tissues.

Vitek et al (1994) have reported that beta amyloid peptides (βAP)aggregate slowly under normal physiological conditions whereas AGEmodified (βAP) showed a much more rapid aggregation. Plaque numbersincrease in association with neuronal degeneration and cognitive declinein AD. Aggregated but not monomeric βAP is actively neurotoxic. Henceinterference with the process by which AGE formation enhances βAPaggregation or inhibition of AGE formation or AGE breaker therapy willprovide new therapeutic opportunities to reduce the pathophysiologicalchanges associated with Alzheimer's disease.

Hence AGE inhibitors/breakers would be beneficial in reducing theaggregation of βAP, leading to the prevention/treatment of Alzheimer'sdisease.

Li et al (1996) have provided evidence for an interrelationship betweentwo key manifestations of physiological aging in the rat cardiovascularand renal decline and the spontaneous age associated biochemical processtermed advanced glycation thought to contribute to progressive tissuedamage and organ failure. In their study aminoguanidine (an AGEinhibitor) was found to significantly prevent tissue damage as a resultof inhibiting AGE formation. Lower tissue AGE burden in rats as a resultof aminoguanidine administration was found to preserve an altogethermore satisfactory level of cardiovascular and renal function asevidenced by the generally healthier appearance of old rats treated byaminoguanidine as compared to the untreated age and weight matchedcontrols. Hence AGE inhibitors could be used for the prevention of agingrelated disorders.

The nonenzymatic browning reaction, which occurs in the oral cavity,results in the discoloration of teeth. Anti-plaque agents such aschlorhexidine have been reported to accelerate the non-enzymaticbrowning reaction and further the staining of teeth. (Nordbo, J. Dent.Res., 58, p. 1429 (1979)). Nordbo has proposed that chlorhexidineresults in tooth staining in two ways: first, by increasing theformation of pelicle which contains more amino groups, and secondly, bycatalysis of the Maillard reaction leading to colored products.

The ability of inhibitors of non-enzymatic browning reaction to preventthe discoloration of protein on a surface, such as that which occurs onthe tooth surface has been demonstrated with in vitro experiments inU.S. Pat. No. 5,137,916; U.S. Pat. No. 5,272,176.

Compounds that have the ability to inhibit or reverse AGE have beenclaimed to be useful for the inhibiting or reversing the discolorationof teeth resulting from non-enzymatic browning in the oral cavity. (U.S.Pat. No. 5,272,176; U.S. Pat. No. 5,853,703)

All these evidences point out to a common underlying mechanism for thepathophysiological conditions associated with diabetes and that is theformation of Advanced Glycation Endproducts. As the total tissue burdenof AGE increases, the severity of the pathological symptoms tooincrease. On the other hand, if the quantum of AGE is controlled by thecompounds like Aminoguanidine, the progression of disease is alsoretarded. In the present invention, the inhibition of Advanced GlycationEndproducts is described.

Renal disease is a leading cause of death and diability in diabetes.Chronic dialysis and renal transplantation are quite routine in patientswith renal failure due to diabetes. Peritoneal Dialysis (PD) works onthe same principle as hemodialysis, but the blood is cleaned whileinside the body rather than through a machine. The major difference inperitoneal dialysate formulations as compared to hemodialysis in theamount of higher glucose concentrations used as an osmotic agent (1.5,2.5 or 4.25 g/dL). High glucose formation in humans is associated withthe progressive formation of Advanced Glycosylation End-products (AGE's)that damage organ function. AGE's contribute to the development ofabnormal fibrous tissue and reduces the ability of the peritoneum tofilter fluids, leading to a failure of the PD procedure.

The compounds which can alter the AGE contents of the tissue could beused to prevent this process and other medical complications arisingfrom the formation of AGE's. Use of an AGE breaker or inhibitor in thedialysis fluid would inhibit formation of abnormal fibrous tissue andthereby facilitate peritoneal dialysis procedure. Accordingly thecompound of the invention can be used for preparation of dialysis fluidfor peritoneal dialysis of a diabetic patient.

Reducing the tissue burden of AGE is expected to reverse theseconditions, whereas preventing accumulation upto critical mass couldprevent the condition from occurring. These conditions are listedbellow:

a. vascular and neuro-vascular complications,

b. nephrological disorder,

c. neurological disorder,

d. atherosclerosis,

e. retinal disorder,

f. dermatological disorder,

g. non-enzymatic browning of oral cavity,

h. endothelial or other organ dysfunction,

i. growth impairment,

j. inflammatory disorder,

k. immunological disorder,

l. oxidative stress,

m. aging and diabetic complication,

n. alzheimer disease,

o. restenosis, abnormal tissue hindrance in peritoneal dialysis,

p. abnormal tissue hindrance in peritoneal dialysis and

q. erectile dysfunction.

The compounds showing the activity towards breaking/inhibiting AGE canalso be useful for their cosmetic utility.

Health, resilience and youthful appearance of the skin depends, amongother things, on several key classes of biological molecules. The keyskin molecules are collagen and elastin. Collagen is a protein, formingthe structural grid that holds other skin structures. It gives the skinits strength and durability. As any other protein, collagen is composedof amino acids. However it is unusually rich in a few specific aminoacids; proline, hydroxy proline, lysine and glycine. Elastin is also aprotein, more stretchable than collagen and helps to maintain skinresilience and elasticity. It contains two special amino acids:desmosine and isodesmosine. When both elastin and collagen are at scarceand damaged, the skin looses its shape after being stretched or foldedleading to wrinkles and facial sag that happens during the process ofaging.

Most modern theories of aging have centered around the notion thatage-related deterioration is primarily due to structural and functionalmodifications of cellular constituents. The currently popular hypothesisare the Free Radical, Glycation or Maillard theories of aging. The firsthypothesis proposes that age-related effects are due to free radicalreactions that damage cellular constituents. “Free radical” refers to anunstable molecule that has an unpaired or odd electron in an outerorbit, which indiscriminately react with other molecules causing lipid,DNA and protein damage. The latter hypothesis propose that the primarycause of aging is cellular damage resulting from the modification ofmacromolecules induced by non-enzymatic glycation and Maillard reactionsto form advanced glycosylation end-products (AGEs). Non-enzymaticglycation is the chemical attachment of sugars to protein thateventually causes protein cross linking, which is irreversible. Althoughthese hypothesis were formulated independently, it suggests that freeradicals, glycation, and Maillard reactions may in fact representpartially interactive elements of a single, more complex biochemicalpathway, and that age-related deterioration is produced by the sum ofthe damages induced by all three hypotheses, and by their interactions.

Skin, a highly differentiated and complexly structured organ, isparticularly vulnerable to free radical damage on exposure to UVradiation resulting in an increased accumulation of AGEs on the skin aswell as an increased production of singlet oxygen and super oxideradicals which damage the important skin molecules such as collagen andelastin. Under such situations an anti-oxidative condition through freeradical scavenging would certainly enable the skin to maintain itsnormal resilience and integrity against damage.

Hence, the present invention is directed towards a cosmetic applicationwith an active molecule capable of reversing the AGE cross links andcreating an anti-oxidative environment in tissues through its AGEbreaking and free radical quenching actions, thereby significantlyslowing down the aging manifestations.

The skin is the largest organ in the body, comprising about 15% of thebody weight. In terms of chemical composition, the skin is about 70%water, 25% protein and 2% lipids. The remainder includes trace minerals,nucleic acids, glycosoaminoglycans, proteoglycans and numerous otherchemicals.

The skin consists of 3 main layers: Epidermis, dermis, subcutaneoustissue. The epidermis is the first barrier between us and the outsideworld. This layer consists of 3 types of cells; keretinocytes,melanocytes and langerhans cells. The dermis is the middle layer of theskin, the thickest of the skin layers and comprises a tight, sturdy meshof collagen (type-I and III) and elastin fibers which are the criticallyimportant skin proteins. The dermis also consists of fibroblasts,capillaries, lymph nodes, sebaceous glands, sweat glands and hairfollicles. The subcutaneous tissue is the innermost layer of the skincomprising mainly of adipocytes, acts as a shock absorber and heatinsulator, protecting underlying tissues from cold and mechanicaltrauma.

Aging is a biological phenomenon which is symbolized by wrinkles andsagging skin. As a person ages, skin cells divide more slowly, and theinner skin, or dermis, starts to thin. Fat cells beneath the dermisbegin to atrophy, and the underlying network of elastin and collagenfibers, which provides scaffolding for the surface layers, loosens andunravels. Skin loses its elasticity; when pressed, it no longer springsback to its initial position but instead sags and forms furrows. Theskin's ability to retain moisture diminishes; the sweat- andoil-secreting glands atrophy, depriving the skin of their protectivewater-lipid emulsions. As a consequence, the skin becomes dry and scaly.In addition, the ability of the skin to repair itself diminishes withage, so wounds are slower to heal. Frown lines (those between theeyebrows) and crow's feet (lines that radiate from the corners of theeyes) appear to develop because of permanent small muscle contractions.Habitual facial expressions also form characteristic lines, and gravityexacerbates the situation, contributing to the formation of jowls anddrooping eyelids. Since the skin represents the most visible organ ofthe aging, there is increasing interest in the physiology and reversalof wrinkles, elastoses and senile xerosis. Cutaneous aging is a complexphenomenon consisting of genetically determined intrinsic and extrinsicaging factors (Boni R, Burg G: Schweiz Med Wochenschr (2000) Sep. 9; 130(36): 1272-8).

Mainly, there are two biologically independent aging processes thatoccur simultaneously, which account for the major changes seen in skinover time.

1. Extrinsic aging or Photoaging/External Factors and

2. Innate or Intrinsic aging/Internal Factors

Extrinsic aging or Photoaging, which results when skin is exposed to theelements like Ultraviolet (UV) radiation, Chemical Pollutants,Allergens, Mechanical damage, etc. Extrinsic aging is primarily causedby ultraviolet radiation of the sun.

Intrinsic aging affects skin by slow, irreversible degeneration oftissue. The factors causing intrinsic aging are genetic, nervous(stresses), immune, hormone disorders and others. Intrinsic aging can beobserved over the entire surface of the body, including skin protectedfrom ultraviolet radiation of sun. The phenomenon of glycation asdiscussed above plays a serious part in intrinsic aging. Proteins fromdermis, elastin and collagen react with sugars in the body, especiallyglucose to result in the binding together of collagen fibers and thesynthesis of free radicals. This modifies the structure of the skincausing it to loose its suppleness and become more rigid. Thus, the mostnoticeable changes on facial skin result from a combination of intrinsicand extrinsic aging processes.

Basically two factors—free radicals and AGE formation are the prominentaccelerators of skin wrinkles. The Maillard theory of Skin aging datesback to 1912 when Maillard found that reducing sugars such as glucoseand ribose react with proteins to form brown pigments. The Maillardreaction is a series of complex reactions that cause the cross-linkingof protein via the interaction of reducing sugars with amino groups ofproteins to form stable Amadori products, which subsequently cross-linkto form Advanced Glycation End products (AGE). Another property ofcritical biological significance is the observation that the Amadoriproducts continue to cross-link and polymerize even in the absence offree glucose. Protein crosslink is important since it is responsible fordeep wrinkling in the dermis. The formation of AGE crosslinks is also anatural part of the aging and all the processes where protein aging is aserious detriment. During the aging process reducing sugar chemicallyattaches to the skin's support proteins like elastin and collagen,causing them to become gradually rigid and slowing their renewal. Thisnon-specific and non-enzymatic attachment of the sugar to collagen andelastin lead to the formation of AGE which continues to cross-link andpolymerize even in the absence of free glucose. The studies on the roleof AGEs in aging collagen using scanning force microscope reveal that inthe presence of an increased concentration of AGEs, significantstructural alterations have been observed in the collagen fibrils of oldrats (Odetii P, Aragno I, et al. Gerontology (1998); 44 (4); 187-91). Asa result of this aging process, collagen loses its elasticity and theskin develops wrinkles.

The covalent binding of glucose to the amino group of protein alone isnot sufficient to account for structural changes observed in collagen.Oxygen radicals formed during glucose oxidation, and glycated proteinoxidation may be involved directly in the formation of AGEs and collagencross-linking. In vitro studies demonstrate that the presence of oxygenis indispensable for the advanced glycation and cross-linking ofcollagen. Antioxidative condition and free radical scavengers have beenproven to inhibit or slow down the formation of AGEs and thecross-linking of collagen. It is also known that free radical scavengersare essential in protecting the epidermis from damage by free radicalsgenerated both by environmental and endogenous factors (Pugliese P T,Dermatol. Nurs (1998) Dec: 10 (6): 401-16; quiz 417-18).

Skin, which has a highly differentiated and certainly complexorganizational structure, is particularly vulnerable to free radicaldamage because of its contact with oxygen and other environmentalstimuli (Calabrese V, Scapagnini G et. al., Drugs Exp. Clin Res. (1999);25(6): 281-7). Studies have proved that UV radiation increases theformation of AGEs on collagen, elastin and other skin proteins. It formsa vicious cycle by increasing the accumulation of AGEs on the skin aswell as increased production of singlet oxygen and super oxide radicals,which damage the skin protein.

With recent years, substantial progress has been made in unraveling theunderlying mechanisms of photoaging. Induction of matrixmetalloproteinases as a consequence of activator protein (AP)-1 andNuclear factor (NF)-kB activation as well as mutations of mitochondrialDNA have been identified recently (Berneburg M, et. al. PhotodermatolPhotoimmunol. Photomed (2000) Dec. 16 (6): 238-44). In the early stageof glycation the condensation of reducing sugars such as glucose withamino groups of proteins generates UVA photo generated singlet oxygenfree radicals. It is reported that AGE is an important factor forpromoting photoaging in the skin via generation of active oxygen speciesinvolving O₂ ⁻, H₂O₂ and —OH (Masaki H. et. al., Biochem Biophys. Res.Commun (1997) June 18: 235). On the basis of invitro fibroblast studiesa possible mechanism is proposed in which AGEs under UVA irradiationgenerate active oxygen species involving O₂ ⁻, H₂O₂ and OH while the OHspecies place a harmful role in promoting cell damage (Hitoshi Masakiet. al. Biochemica et Biophysica Acta 1428 (1999) 45-56). These radicalsdisrupt the natural balance of the skin by stimulating the skin cells tosynthesize metalloproteinases. The metalloproteinase enzymes degradecollagen without synthesizing anti-metalloprotenases that keeps a checkon the skin protein degradation, which is a normal biological response.The unbalanced production of metalloproteinase overanti-metalloprotenases induced by singlet oxygen free radicals leads tobreak down of collagen and elastin of the skin. This is followed byimperfect wound repair of damaged collagenous matrix and accumulation ofelastotic material, as a consequence the skin sags and wrinkles.

Due to the exposure of AGEs to UV A radiations, the generation of superoxide anion gets enhanced. This is accomplished through cellularelectron transfer chain in which UV A-AGEs energy enhances the passingof electrons onto ground state oxygen. This leads to enhanced formationof super oxide. anion during Adenosine Triphosphate (ATP) synthesis. Anenzyme super oxide dismutase converts the super oxide anion intohydrogen peroxide and oxygen. Finally, the catalytic action of iron andcopper transforms hydrogen peroxide into toxic hydroxyl radical causesthe degradation of skin collagen and elastin which is followed byimperfect wound healing and solar scar develop that photoage the skin.

The shelves in the cosmetics market are full of products treatingextrinsic aging, but there is still a vacuum for a product, whichtargets intrinsic aging by inhibiting AGE in skin support proteins.

The ability to inhibit the formation of Advanced Glycation End products(in skin support proteins, like collagen) along with AGE breakeractivity and Free Radical Scavenging activity, carries with itsignificant implications in treatment of Skin aging and wrinkles etc.

Thus, using the molecules, which can alter the presence of AGE, it ispossible to prevent the signs of skin aging and wrinkle formation etc.,and using them for cosmetic applications.

Experience shows that skin aging and wrinkle formation occur in-spite ofgood skin care. Hence, there is a need for development of an agent toprevent or treat aging of skin caused by formation of AGE. The compoundsof the present invention are non-peptide, capable of modifying the AGEcross-link, formation in Collagen and Elastin. The compounds of theinstant invention can be formulated along with other agents into acosmetic preparation.

To prevent or delay skin wrinkles, it is important to inhibit formationof AGE, to reverse the already formed AGE as well as lower the oxidativestress by means of an antioxidant or free radical scavanger. Essentiallya molecule that inhibits AGE; breaks AGE and slows down the formation ofAGE and prevents collagen degradation, would be an ideal candidate forcosmeceuticals. The molecules of the instant invention exhibit theproperties of being an AGE inhibitor and a potent AGE breaker well asfree radical scavenger which make them most suitable for cosmeticapplications.

Free radicals are atoms or molecules that have one or more unpairedelectrons in their atomic structures and are highly reactive. Freeradicals—reactive oxygen species (ROS)—are produced continuously inmammalian systems as a consequence of normal metabolic processes.Exogenous sources of ROS include exercise, pollution (especiallycigarette smoke and car exhaust), alcohol, sunlight, and drugs (likeanesthetics). Although free radicals have an important role in normalphysiologic mechanisms, the excessive production of ROS results inoxidative stress—the terms usually applied to the out come of oxidativedamage to biologically important molecules, such as protein, lipids, andnucleic acids. Proteins have long been known to be susceptible tooxidation by ROS. Aromatic amino acids like cystine, and disulfide bondsare particularly vulnerable. All biological materials contain a varietyof polyunsaturated fatty acids, which are predominantly located inmembrane lipids. They are highly susceptible to damage by ROS.

The group of compounds known as antioxidants (also referred to as “freeradical scavengers”) is the major defense against oxidative stress.These compounds function to protect membrane and cytosolic componentsagainst damage from ROS. Primary antioxidants, which prevent theformation of new radical species, include enzyme systems such assuperoxide dismutase (SOD) and glutathione peroxidase (GSH Px).Secondary antioxidants trap radical species, thus preventing chainreactions, and include nutrients such as vitamin E, vitamin C, taurineand β-carotene. The final line of antioxidant defense is provided by therepair systems such as the enzyme methionine sulfoxide reductase thatregenerates methionine residues within oxidized proteins and restoresfunction.

Endogenous oxidative damage to cellular components, primarily proteins,lipids, and DNA is thought to contribute to the pathogenesis of numerouschronic diseases. The association between compromised antioxidantstatus, indices of oxidative damage, and clinical conditions likediabetes mellitus, asthma, chronic renal failure, hepatitis, colitis,atopic dermatitis, arthritis and various degenerative disorders is nowwell documented. There is considerable circumstantial evidence linkingdiminished antioxidant status including enzymes and nonezymaticscavengers, to increased oxidative damage and disease severity.

There is need of the molecules with ability to break/inhibit the proteincross linking, in addition of having anti-oxidant activity so that apartfrom their use in several disease conditions where oxidative stressplays vital role in the pathogenesis, they can be effectively used forcosmetic applications as mentioned below:

a) reversal and prevention of wrinkles,

b) reversal and prevention of fine lines,

c) promotion of epidermal growth,

d) photo protection of skin,

e) reversal and prevention of skin discoloration,

f) reversal and prevention of age spots,

g) conditioning and prevention of dry spot,

h) reversal and prevention of stretch marks,

i) reversal and prevention of blemishes,

j) skin care and conditioning,

k) reversal and prevention of senile xerosis,

l) conditioning and prevention of sun burns,

m) preventing and reversing the loss of collagen,

n) improving skin texture,

o) improving skin tone,

p) enhancing of skin thickness,

q) decreasing pore size,

r) restoring skin luster,

s) minimising signs of fatigue,

t) reducing acne,

u) treatment of Telangiectasia and

v) improving aesthetic appearance of hair and nails.

Pharmaceutical Application of the Free-Radical Scavenging (Anti-Oxidant)Property of the Molecules.

Apart from the use of the compounds for cosmetic applications based ontheir AGE-breaking/AGE inhibiting and free-radical scavengingactivities, the latter activity of these compounds can be used instrategies directed at control of oxidative stress for effectivemanagement of conditions discussed below:

Neuro-Degenerative Disorders such as Alzheimer's Disease (A.D.),Parkinson's Disease (P. D.), Huntington's Disease (H.D.), Motor NeuronDisease (M.N.D), Prion Disease

As people age, their antioxidant levels diminish and these low levelsare directly linked to the many diseases associated with aging such asAlzheimer's and Parkinson's disease. One of the leading hypotheses isthat oxidative stress induced by Relative Oxygen Species (ROS) damagesessential components of the neurons, resulting ultimately in theneuronal death. Oxidative stress is involved in various divergent eventsleading to neuronal damage, including an increase in membrane rigidity,DNA strand break, and impairment in glucose uptake. Several potentialsources of oxidative stress in different neurodegenerative disordershave been well identified [Munch G, et al. 1998].

In A.D. mitochondrial dysfunction, amyloid beta mediated processes;transition metal accumulation and genetic factors are responsible forthe redox imbalance [Smith M A, et al 2000].

Point mutations in Superoxide Dismutase enzymes are known in thefamilial form of MND.

Disturbances of neuronal energy metabolism have been implicated as apathogenetic mechanism for H.D. [Browne S E, et al. 1999]

Diabetes and Diabetic Vascular Complications (DVCs)

The cause of oxidative stress in diabetes is not yet fully understoodbut is thought to be due to mitochondrial dysfunction, direct enzymeinhibition by hyperglycemia, auto-oxidation of glucose, and activationof nicotinamide-adenine dinucleotide phosphate (NADPH)-oxidase.Oxidative stress in diabetes is also increased due to weakened defensesdue to reduced endogenous antioxidants. The oxidative stress manifestsitself as elevated concentrations of lipid peroxidation products,erythrocyte fragility, and decreases in the antioxidant enzyme systems(CAT, GSH Px, SOD). Recent studies also have shown a positivecorrelation between blood glucose concentration and oxidant-inducedlymphocyte DNA damage [E. J. Harper The 24^(th) Annual WALTHAM®/OSUSYMPOSIUM]

ROS are generated during glucose oxidation and formation of advancedglycosylation end products (AGE). Evidence has accumulated indicatingthat the generation of ROS plays an important role in the development ofDVCs. Many biochemical pathways associated with hyperglycemia such asadvanced glycosylation, glucose auto oxidation, and polyol pathway canincrease the production of free radicals. Hyperglycemia in diabeticpatients leads to excess auto-oxidation of glucose thereby reducingmolecular oxygen and yielding oxidizing intermediates such as superoxideions (O₂ ⁻), hydroxyl radicals (.OH), and hydrogen peroxide (H₂O₂). Freeradicals accelerate the formation of advanced glycosylation end products(AGE), because fragmentation and conformational changes occurring duringglycosylation and glucose oxidation have been shown to be dependent uponfree radicals. AGEs in turn supply more free radicals; this process istermed as oxidative glycosylation or glycoxidation. These free radicalsimpair vascular relaxation by inactivating or quenching nitric oxide(NO) and also adversely affect the endothelial function. Evidence alsosuggests that Maillard reaction acts as an amplifier of oxidative damagein aging and diabetes [D. Guigliano et al, 1996].

Intestinal Diseases

Oxidative stress is an important cause of tissue injury that occurs ininflammation and ischemia. Intestinal ischemia, radiation enteritis,inflammatory bowel disease, and promotion of gastric and colorectalcancers are some of the gastro-intestinal conditions where oxidativestress is implicated in the pathogenesis.

Liver Diseases

Alcoholic liver disease—Ethanol induces an increase in lipidperoxidation either by enhancing ROS or decreasing the level ofendogenous antioxidants. Ethanol also induces variety of cytochrome P450enzymes in microsomes and xanthine oxidases in cytosol. The role ofthese enzymes in the generation of oxidative stress has been wellestablished in various studies [Ishii H, et al. 1997].

Chronic hepatitis C— Enhanced oxidative stress initiates a fibrogenesiscascade in the liver of patients with chronic hepatitis C. Evidences arecoming up supporting an oxidative stress pathway leading to activefibrogenesis in chronic hepatitis C. This fibrogenesis cascadecharacteristic of severe chronic hepatitis C (e.g., oxidative stress,induction of c-myb, activation of stellate cells, and collagen geneexpression) is stimulated by ROS.

Cancers

Oxidative damage to DNA is a result of interaction of DNA with ROS, inparticular the hydroxyl radical. The hydroxyl radicals produce multiplemodifications in DNA. Oxidative attack by OH radical on the deoxyribosemoiety leads to the release of free bases from DNA, generating strandbreaks with various sugar modifications and simple abasic (AP) sites.

ROS also interact with and modify cellular protein, lipid, and DNA,which results in altered target cell function. The accumulation ofoxidative damage has been implicated in both acute and chronic cellinjury including possible participation in the formation of cancer.Acute oxidative injury may produce selective cell death and acompensatory increase in cell proliferation. This stimulus may result inthe formation of newly initiated preneoplastic cells and/or enhance theselective clonal expansion of latent initiated preneoplastic cells.Similarly, sublethal acute oxidative injury may produce unrepaired DNAdamage and result in the formation of new mutations and, potentially,new initiated cells. ROS, therefore, can have multiple effects in theinitiation stage of carcinogenesis by mediating carcinogen activation,causing DNA damage, and interfering with the repair of the DNA damage.

Benefits of various antioxidants in preventing or treating followingcancers have been extensively studied.

1) Lung cancer

2) Colorectal cancer

3) Cervical cancer

4) Breast cancer

5) Malignant melanoma

Oxidative Stress in Cardiac Diseases

Lifelong high levels of antioxidant nutrients are supposed to protectagainst the development of heart disease. High doses of antioxidants inthe month following an acute heart attack have been shown tosignificantly reduce the number of deaths, as well as the extent ofcardiac damage in non-fatal cases.

It is currently thought that increase in oxidative stress is involved inthe pathophysiology of endothelial dysfunction that accompanies a numberof cardiovascular risk factors including hypercholesterolemia,hypertension and cigarette smoking. It also plays a pivotal role in theevolution of clinical conditions such as atherosclerosis and heartfailure. Oxidative stress can activate redox-sensitive kinase cascadesand transcription factors such as NF_(K)B and AP-1, with resultingincreases in the expression of factors associated with an inflammatoryresponse and cellular proliferation. There are three enzyme systemsproducing reactive oxygen species in the vascular wall: NADH/NADPHoxidase, xanthine oxidoreductase, and endothelial nitric oxide synthase(Zalba G. et. al, 2000, Rosenfeld M E, 1998).

Atherogenesis is regarded as the outcome of interactions among multiplestimuli. Endothelial dysfunction plays a key role in the development ofatherosclerosis. Elevated homocysteine concentrations are associatedwith rapid onset of endothelial dysfunction, which is another mechanismby which increased oxidative stress contributes to atherosclerosis.Oxidation of low-density lipoprotein plays an important role at severalsteps in atherogenesis. Oxidative stress also activates NF_(K)B, whichinduces expression of genes controlling cytokine expression andleukocyte adhesion to vascular wall. (Maxwell, et al. 1997).

Animal studies have provided evidence by suggesting that free radicalsmay promote thrombosis, directly damage vascular cells and othertissues, and interfere with vasomotor regulation with the clinicalsequelae of myocardial infarction and ischemic stroke.

In tissues where oxygen supply becomes used up following ischemia, as inmyocardial ischemia, the enzyme xanthine oxidase is changed to a formthat has potential to reduce oxygen to superoxides. On readmission ofoxygen e.g. by reperfusion there is a burst of free radical generation.ROS are formed at an accelerated rate in post-ischemic myocardium. Thusbiochemical damage due to free radicals contributes to the ischemicinjury.

Oxidative stress also seems to be one of the mechanisms that may producemembrane defects and result in intracellular calcium overload, andcardiac contractile dysfunction in the stunned myocardium.

Macular Degeneration and Cataract

Oxidative damage to lens of the eye with increase in age has a majorcontribution in cataract formation. Macular degeneration is also beingrecognized as a consequence of oxidative damage.

HIV Disease

Perturbation of anti-oxidant defense system has been observed in varioustissues in HIV patients. Oxidative stress may contribute to severalaspects of HIV disease pathogenesis such as viral replication,inflammatory response, and decreased immune cell proliferation, loss ofimmune function, apoptosis, chronic weight loss. Antioxidants may offera promising treatment to HIV patients.

Chronic Obstructive Pulmonary Diseases (COPD)

Alteration in the alveolar and lung metabolism of glutathione is widelyrecognized as a central feature of many inflammatory lung diseasesincluding COPD. These changes are a result of the alteration in the geneexpression of the gamma-glutamyl cystine synthase (Gamma-GCS), therate-limiting enzyme in glutathione synthesis. Oxidative stress isimplicated in the pathogenesis of COPD, since it results in inactivationof anti proteinases, airspace epithelial injury, mucus hypersecretion,increased influx of neutrophils into the lungs, transcription factoractivation and gene expression of pro-inflammatory mediators [MacNee W,et al. 2001].

Renal Disease

ROS have been implicated not only in the genesis of different forms ofrenal disease, predominantly experimentally induced glomerulonephritis,but also in different forms of acute renal failure.

Asthma

Although the pathogenesis of asthma is not fully defined, a typicalfeature is an increase in the number of inflammatory cells in the lung.Such cells generate ROS, which are involved in the pathophysiology ofasthma, including airway smooth muscle contraction, increased airwayreactivity, and increased vascular permeability.

Effect of Antioxidant Status on Immunologic Function

The immune system is particularly sensitive to oxidative stress,primarily because immune cells rely heavily on cell-to-cellcommunication to work effectively. Peroxidation of cell membranescompromises membrane integrity and disrupts intracellular signaling.

Cataract

Oxidative damage to lens of eye with increase in age has been a majorcontribution in cataract formation.

Thus, by scavenging the free radicals, the following diseases can bemanaged.

1) Neurodegenerative disorders

-   -   (a) Alzheimer's Disease    -   (b) Parkinson's Disease    -   (c) Huntington's Disease    -   (d) Motor Neuron Disease    -   (e) Prion Disease

2) Diabetes and Diabetic Vascular Complications

3) Intestinal Diseases

-   -   (a) Intestinal Ischemia    -   (b) Radiation Enteritis    -   (c) Inflammatory Bowel Disease    -   (d) Gastric and Colorectal Cancers

4) Liver Diseases

-   -   (a) Alcoholic Liver Disease    -   (b) Chronic Hepatitis C

5) Cancers

-   -   (a) Lung Cancer    -   (b) Colorectal Cancer    -   (c) Cervical Cancer    -   (d) Breast Cancer    -   (e) Malignant Melanoma

6) Cardiac Diseases

-   -   (a) Atherosclerosis    -   (b) Myocardial Infarction    -   (c) Ischemic Stroke    -   (d) Endothelial dysfunction

7) Opthalmic Disorders

-   -   (a) Cataract formation    -   (b) Macular degeneration

8) HIV Disease

9) Respiratory Diseases

-   -   (a) Chronic Obstructive Pulmonary Diseases (COPD)    -   (b) Asthma

10) Renal Diseases

-   -   (a) Glomerulonephritis    -   (b) Acute Renal failure

SUMMARY OF THE INVENTION

The first objective of the present invention is to provide a new classof five membered heterocyclic ring compounds which are useful for themanagement of diabetes and aging related vascular complications andparticularly in the treatment of complications of diabetes mellitus andother aging related conditions such as vascular and neurovascularcomplications including kidney disease, nerve damage, atherosclerosis,retinopathy, inflammatory disorders, immunological disorders, oxidativestress and dermatological & cosmetic indications. The invention alsoextends the method to reverse the discoloration of teeth resulting fromnonenzymatic browning in the oral cavity which comprises administrationof an amount effective to reverse the pre-formed advanced glycosylationcrosslinks.

The second object of the present invention is to provide compounds offive membered heterocyclic ring compounds, which exhibit AGE breakingand inhibiting activities.

The third object of the present invention is to provide a method ofpreparation of compounds of five membered heterocyclic ring compounds,which exhibit AGE breaking and inhibiting activities.

The fourth object of the invention is to provide pharmaceuticalcompositions with a new class of compounds of five membered heterocyclicring compounds, according to the invention and their pharmaceuticallyacceptable salts in combination with suitable carriers, solvents,excepients, diluents and other media normally employed in preparing suchcompositions.

The fifth object of the invention is to provide a method of treatment ofa diabetic patient by administration of the compounds of the invention,either singly or in combination with drugs for anti-diabetic therapy, orpharmaceutically acceptable salts thereof in required dosage inadmixture with pharmaceutically acceptable diluent, solvent, excepients,carriers or other media as may be appropriate for the purpose.

The sixth object of the invention is to provide a new class of compoundshaving a) free radical scavenger activity b) AGE breaker activity and c)AGE inhibitor activity in the same molecule.

The seventh object of the invention is to provide a cosmetic compositioncomprising these compounds as active ingredients.

The eighth object of the invention is to provide a process for makingthe cosmetic composition.

The ninth object of the invention is to provide a method for cosmeticapplication by applying the cosmetic composition of the invention.

The tenth object of the invention is to provide a pharmaceuticalcomposition useful for scavenging free-radicals from the body cells.

The eleventh object of the invention is to provide a method forscavenging free radicals from the body cells of a mammal.

The twelfth object of the invention is to provide a method of treatmentof diseases caused by accumulation of free radicals in the body cells ofa mammal.

The thirteenth object of the invention is to provide a method forinhibiting AGE and also a composition for inhibiting AGE in a mammal.

Another object of the invention is to provide a dialysis fluid usefulfor peritoneal dialysis of a diabetic patient.

The invention also provides for a method of cosmetic treatment byapplying the composition as above. The invention further provides apharmaceutical composition useful for scavenging free radicals from thebody cells of a mammal comprising the compound as defined above or itspharmaceutically acceptable salts in admixture with a pharmaceuticallyacceptable carrier, diluent excipient or solvent.

The invention further provides a method of scavenging free radicals fromthe body cells of a mammal by administering the pharmaceuticalcomposition as mentioned above or a method of treatment of diseasescaused by accumulation of free radicals by administering the saidcomposition.

The invention in addition provides a method for inhibiting AGE and acomposition for inhibiting AGE by use of the compounds of invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a new class of AGE-breakers of formula I

whereinR1 is alkyl or aryl group;Y is selected from the group consisting of sulfur, oxygen, nitrogen oralkyl;A and B are independently selected from nitrogen, sulfur, oxygen orcarbon to form heteroaromatic ring system;R2, R3 and R4 are independently selected from the group consisting of F,Cl, Br, I, OR₇, NO₂, alkyl, aryl including heteroaryl, formyl, acyl,C(O)NR₆R₇, C(O)OR₆, NR₆R₇, N—C(R₆)(R₇), SR₆, SO₂NH₂, SO₂ alkyl, SO₂aryl;R₂, R₃ and R₄ might be optionally joined together to form a ring system;If quaternized, R₅ is independently selected for the group consisting ofalkyl or aryl; if not quaternized, R₅ is null, and X is null;R₆ is independently selected from the group consisting of H, alkyl andaryl including heteroaryl provided R₆ might be different for R₂, R₃ andR₄ in the same compound;R₇ is independently selected from the group consisting of H, alkyl andaryl including heteroaryl and in each case optionally different fromsubstituent R₆, provided R₇ might be different for R₂, R₃ and R₄ in thesame compound;If quaternized, X is selected from group consisting of a halide ion,acetate ion, perchlorate ion, sulfonate ion, oxalate ion, citrate ion,tosylate ion, maleate ion, mesylate ion, carbonate ion, sulfite ion,phosphoric hydrogen ion, phosphonate ion, phosphate ion, BF₄ ⁻ and PF₆with proviso that when two alkyl groups are present on the same carbonor nitrogen, they are optionally linked together to form a cyclicstructure.

As used herein, “alkyl” refers to an optionally substituted hydrocarbongroup joined by single carbon-carbon bonds and having 1 to 8 carbonatoms joined together. The alkyl hydrocarbon group may be linear,branched or cyclic, saturated or unsaturated. The substituents areselected from F, Cl, Br, I, N, S, O and aryl. Preferably, no more thanthree substituents are present.

As used herein “aryl” refers to an optionally substituted aromatic groupwith at least one ring having a conjugated pi-electron system,containing up to two conjugated or fused ring systems. Aryl includescarbocyclic aryl, heterocyclic aryl and biaryl groups, all of which maybe optionally substituted. The substituents are selected from F, Cl, Br,I, N, S, O and straight chain or branched C₁-C₆ hydrocarbon.

In a preferred embodiment the invention provides a new class of AGEbreaker, AGE inhibitor and free radical scavengers of formula (I) andtheir pharmaceutically or cosmetically acceptable salts

wherein,R₁ is hydrogen or selected from linear or branched (C₁-C₁₂) alkyl,(C₂-C₁₂) alkenyl, (C₃-C₇) cycloalkyl, (C₅-C₇) cycloalkenyl,bicycloalkyl, bicycloalkenyl, heterocycloalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl and wherein one or more heteroatoms whenpresent are independently selected from O, N, or S and is optionallysubstituted, wherein the substituents are selected from a first groupconsisting of halogen, hydroxy, nitro, cyano, amino, oxo and oxime orfrom a second group consisting of linear or branched (C₁-C₈) alkyl,(C₃-C₇) cycloalkyl, alkylcycloalkyl, perhaloalkyl, perhalocycloalkyl,aryl, aralkyl, alkylaryl, alkylheteroaryl, aralkoxylalkyl, perhaloaryl,alkylheterocycloalkyl, heterocyclyloalkyl, perhaloheterocyclyloalkyl,heteroaryl, heteroaralkyl, alkylaryl, perhaloheteroaryl, acyl,alkoxyalkyl, thioalkyl and thioaryl, wherein the substitutents from saidsecond group are optionally substituted by R₁₀ and are optionally andindependently bridged by —(CO)O—, —(CO)NH—, —NH—, —NR₈—, —O—, —S—,—(SO)—, —(SO₂), —(SO₂)NH—, or —NH(CO)—;Y is selected from the group consisting of null, (C₁-C₁₂) alkyl-Z or(C₂-C₁₂) alkyl, wherein Z is selected from sulfur, oxygen or nitrogen;A and B are independently selected from NH, NR6, sulfur, oxygen orcarbon to form a heteroaromatic ring system;R₂, R₃ and R₄ are independently selected from a first group consistingof hydrogen, halogen, NO₂, N═C(R₈)(R₉), —NR₈R₉, —OR₈, perhaloalkyl,—(CO)NR₈R₉, —(CO)R₈, —(CO)OR₈, —O(CO)R₈, —NH(CO)R₈ or from a secondgroup consisting of linear or branched (C1-C12)alkyl, (C2-C12)alkenyl,(C3-C7)cycloalkyl, (C5-C7)cycloalkenyl, bicycloalkyl, bicycloalkenyl,heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, wherein oneor more members of said second group when present are optionallysubstituted by R10 and wherein one or more heteroatoms when present areindependently selected from O, N, or S;R₅ is null or selected from the group consisting of linear or branched(C₁-C₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₃-C₇)cycloalkyl, (C₅-C₇)cycloalkenyl,bicycloalkyl; CH₂(CO)R₇, CH₂(CO)NHR₈, CH₂(CO)NR₈R₉, and CH₂(CO)OR₇ whichare optionally substituted by R₁₀;R₆ and R₇ are independently selected from the group consisting of linearor branched (C₁-C₈) alkyl, (C₃-C₇)cycloalkyl, alkylcycloalkyl,perhaloalkyl, perhalocycloalkyl, aryl, aralkyl, alkylaryl,alkylheteroaryl, aralkoxylalkyl, perhaloaryl, alkylheterocycloalkyl,heterocyclyloalkyl, perhaloheterocyclyloalkyl, heteroaryl,heteroaralkyl, alkylaryl, perhaloheteroaryl, acyl, benzoyl, alkoxyalkyl,thioalkyl and thioaryl wherein members of said group are optionallysubstituted by R10;R₈ and R₉ are independently selected from the group consisting of linearor branched (C₁-C₁₂)alkyl, alkoxyaryl, alkoxyalkyl, alkoxycycloalkyl,alkoxyaryl, perhaloalkyl, (C₂-C₁₂)alkenyl, (C₃-C₇)cycloalkyl,perhalocycloalkyl, haloheterocycloalkyl, cyanoheterocycloalkyl,perhaloheterocycloalkyl, (C₅-C₇)cycloalkenyl, bicycloalkyl,bicycloalkenyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, perhaloaryl, perhaloheteroaryl wherein substituents ofsaid group are optionally substituted by R₁₀;R₁₀ is selected from halogen, hydroxy, nitro, cyano, amino, oxo,perhaloalkyl(C₁-C₆), or oxime;X is selected from group comprising of a halide ion, acetate ion,perchlorate ion, sulfonate ion, oxalate ion, citrate ion, tosylate ion,maleate ion, mesylate ion, carbonate ion, sulfite ion, phosphorichydrogen ion, phosphonate ion, phosphate ion, BF₄ ⁻ and PF₆ ⁻provided when the groups/substituents are present on same or adjacentcarbon or nitrogen atoms they together may optionally form a five or asix or a seven membered ring optionally containing one or more doublebonds and optionally containing one or more heteroatoms selected from O,N, or S.

The compounds of formula (1) as defined above, is understood to includetheir analogs, their tautomeric forms, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable solvates and theircosmetically acceptable solvates.

The non-limiting examples of pharmaceutically/cosmetically acceptablesalts of the compounds of this invention include but not limited tosalts of the carboxylic acid moiety such as alkali metal salts like Li,Na and K salts; alkaline earth metal salts like Ca and Mg salts; saltsof organic bases for example lysine, arginine, guanidine,diethanolamine, choline, and the like; ammonium or substituted ammoniumsalts and aluminium salts; salts may be acid addition salts for examplesulfates, nitrates, phosphates, perchlorates, borates, hydrohalides,acetates, tartrates, maleates, citrates, succinates, palmoates,methanesulfonates, benzoates, salicylates, hydroxynaphthoates,benzensulfonates, ascorbates, glycerophosphates, ketoglutarates and thelike.

The following novel compounds are suggested by way of example alone ofthe representative compounds of the general formula I as defined aboveand in no way restrict the invention:—

-   a)    1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridinium    bromide (compound 1);-   b) 1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)oxazol-5-yl    pyridinium bromide (compound 2);-   c) 1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(2-thien-2′-yl)-2-oxoethyl    pyridinium-4-thio}methyl-pyrazol-5-yl]pyridinium dibromide.    (compound 3);-   d)    1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(3,5-dimethylpyrazol-1-yl)methyl}pyrazol-5-yl]pyridinium    bromide. (compound 4);-   e)    1-(2-thien-2′-yl-2-oxoethyl)-3-[{3-phenylmethyl}-1-{2-pyridyl}-pyrazol-5-yl]-pyridinium    bromide. (compound 5);-   f)    1-(2-thien-2′-yl-2-oxoethyl)-3-[3{(3,5-dimethylpyrazol-1-yl)methyl-1-pyridyl}pyrazol-5-yl]pyridinium    bromide. (compound 6);-   g)    1-[2-(cyclopropylamino)-2-oxoethyl]3-[3-{(3,5-dimethylpyrazol-1-yl)methyl}-pyrazol-5-yl]-pyridinium    bromide. (compound 7);-   h)    1-{2-(4-nitro-2-thienyl)-2-oxoethyl}-3-[3{(3,5-dimethylpyrazol-1-yl)methyl}-pyrazol-5-yl]-pyridinium    bromide. (compound 8);-   i)    1-(2-cyclopropylamino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium    chloride. (compound 9);-   j) 3,5-bis-[1-(2-thien-2′-yl-2-oxoethyl)-pyridinium-3-yl]-pyrazole    dibromide. (compound 10);-   k)    1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridinium    chloride. (compound 11);-   l)    1-(2-(5′-methyl-2-thienyl)-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridinium    chloride. (compound 12);-   m)    1-(2-thien-2′-yl-2-oxoethyl)3-[1-phenyl,3-{(3,5-dimethylpyrazol-1-yl)methyl)}pyrazol-5-yl]-pyridinium    chloride. (compound 13);-   n)    1-(2-phenyl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]-pyridinium    bromide. (compound 14);-   o)    1-(2-cyclopropylamino-2-oxoethyl)3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridinium    chloride (compound 15);-   p)    1-(2-(4-benzyl-1-piperidinyl)-2-oxoethyl)3-[(3-phenoxymethyl)pyrazol-5-yl]-pyridinium    bromide (compound 16);-   q)    1-(2-phenyl-2-oxoethyl)-3-[(3-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]-pyridinium    chloride (compound 17);-   r)    1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3,-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]pyridinium    chloride (compound 18);-   s)    1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridinium    chloride (compound 19);-   t)    1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3(2-cyclohexylethyl)pyrazol-5-yl]pyridinium    chloride (compound 20);-   u)    1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridinium    chloride (compound 21);-   v)    1-(2-phenyl-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridinium    chloride (compound 22);-   w)    1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-phenylmethyl)pyrazol-5-yl]pyridinium    chloride (compound 23);-   x)    1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridinium    chloride (compound 24);-   y)    1-[2-(1-adamantylamino)-2-oxoethyl]-3-[(3-phenylmethyl)pyrazol-5-yl]pyridinium    chloride (compound 25);-   z)    1-(2-phenyl-2-oxoethyl)-3-[{3-(3,5-dimethylpyrazol-1-yl)methyl)}1-phenyl-pyrazol-5-yl]pyridinium    bromide (compound 26);-   aa)    1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl)-methyl)pyrazol-5-yl]pyridinium    bromide (compound 27);-   bb)    1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridinium    bromide (compound 28);-   cc)    1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridinium    chloride (compound 29);-   dd)    1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridinium    bromide (compound 30);-   ee) pyrazole    1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridinium    chloride (compound 31);-   ff)    1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazole)-1-yl)-5-yl]pyridinium    chloride (compound 32);-   gg)    1-(2-(5-chloro-2-thienyl)-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridinium    bromide (compound 33);-   hh)    1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridinium    chloride (compound 34);-   ii)    1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridinium    chloride (compound 35);-   jj)    1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridinium    bromide (compound 36);-   kk)    1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-(2-cyclohexylethyl)pyrazol-5-yl]pyridinium    bromide (compound 37);-   ll)    1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-phenoxymethyl)pyrazol-5-yl]pyridinium    chloride (compound 38);-   mm) 3-[(3-phenylmethyl)pyrazol-5-yl]pyridine hydrochloride (compound    39);-   nn) 3-[(3-phenoxymethyl)pyrazol-5-yl]pyridine hydrochloride    (compound 40);-   oo) 3-[(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridine    (compound 41);-   pp) 3-[3-(2-cyclohexyl-ethyl)-pyrazol-5-yl]pyridine (compound 42);-   qq)    1-(2-napthyl-2-oxoethyl)-3[(3-phenoxymethyl)pyrazol-5-yl]pyridinium    bromide (compound 43);-   rr) 1-(phenylmethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium    chloride (compound 44);-   ss)    1-(2-thien-2′-yl-2-oxoethyl)-3[(3(-1-naphthyl)pyrazol-5-yl]pyridinium    chloride (compound 45);-   tt)    1-(2-phenyl-2oxoethyl)-3[3(thienyl-2-yl-methyl)pyrazol-5-yl]pyridinium    chloride (compound 46);-   uu)    1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[3(2-phenylethyl)pyrazol-5-yl]pyridinium    chloride (compound 47);-   vv) 1-(2-(5-methyl    2-thienyl)-2-oxoethyl)-3-[3-(3-phenoxypropyl)pyrazol-5-yl]pyridinium    chloride (compound 48);-   ww) 1-(isopropyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium bromide    (compound 49);-   xx)    1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3-thiophenylmethyl)pyrazol-5-yl]pyridinium    chloride (compound 50);-   yy) 1-(2-thien-2′-yl-2-oxoethyl)-3[(3-(N-methyl-indole-3-yl    methyl)pyrazol-5-yl]pyridinium chloride (compound 51);-   zz) 1-(2-napthyl-2-oxo-ethyl)-3[(3-methyl)pyrazol-5-yl]pyridinium    bromide (compound 52);-   aaa) 1-(2-(1,4    benzodioxane-6-yl-amino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium    chloride (compound 53);-   bbb) 1-(2-thien-2′-yl-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]-5    bromo-pyridinium chloride (compound 54);-   ccc)    1-(2-thien-2′-yl)-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]quinolinium    chloride (compound 55) and-   ddd) 3-[(3-phenyl)pyrazol-5-yl)]quinoline (compound 56).

A compoundwise list of substituents of the above compounds in relationto the general structural formula (I) of the compounds as defined aboveis tabulated below: TABLE 1 Comp. No R1 R2 R3 R4 R5 A B Y X  1 Phenyl HH H —CH₂—C(O)-2- NH H —CH₂ —Br thienyl  2 Phenyl H H H —CH₂—C(O)-2- O N—CH₂ —Br thienyl  3 Structure (a) H H H —CH₂—C(O)-2- NH N —CH₂—S —Brthienyl  4 Structure (b) H H H —CH₂—C(O)-2- NH N —CH₂ —Br thienyl  5-Phenyl H H H —CH₂—C(O)-2- N-(2-pyridyl) N —CH₂ —Br thienyl  6 Structure(b) H H H —CH₂—C(O)-2- N-(2-pyridyl) N —CH₂ —Br thienyl  7 Structure (b)H H H —CH₂—C(O)- NH N —CH₂ —Cl NH(Cyclopropyl)  8 Structure (b) H H H—CH₂—C(O)-(5- NH N —CH₂ —Br nitro-2-thienyl)  9 Phenyl H H H —CH₂—C(O)-NH N —CH₂ —Cl NH(Cyclopropyl) 10 Structure (c) H H H —CH₂—C(O)-2- NH Nnull —Br thienyl 11 Phenyl H H H —CH₂—C(O)-2- N-(phenyl) N —CH₂ —Clthienyl 12 Phenyl H H H —CH₂—C(O)-(5- NH N —CH₂ —Cl methyl-2-yl) 13Structure (b) H H H —CH₂—C(O)-2- N-(phenyl) N —CH₂ —Cl thienyl 14 PhenylH H H —CH₂—C(O)- NH N —CH₂ —Br phenyl 15 Phenyl H H H —CH₂—C(O)-N-(phenyl) N —CH₂ —Cl NH(Cyclopropyl) 16 Phenyl H H H —CH₂—C(O)-4- NH N—CH₂—O— —Cl benyzl-piperidin-1-yl) 17 Structure (b) H H H —CH₂—C(O)- NHN —CH₂ —Cl phenyl 18 Structure (b) H H H —CH₂—C(O)-(5- NH N —CH₂ —Clmethyl-thien-2-yl) 19 Phenyl H H H —CH₂—C(O)- N-(phenyl) N —CH₂ —Clphenyl 20 Cyclohexyl H H H —CH₂—C(O)-(5- NH N —CH₂—CH₂— —Clmethyl-thien-2-yl) 21 Cyclohexyl H H H —CH₂—C(O)- NH N —CH₂—CH₂— —ClNH(Cyclopropyl) 22 Cyclohexyl H H H —CH₂—C(O)- NH N —CH₂—CH₂— —Cl phenyl23 Phenyl H H H —CH₂—C(O)- N-(cyclohexyl) N —CH₂ —Cl NH(Cyclopropyl) 24Phenyl H H H —CH₂—C(O)-2- NH N —CH₂—O— —Cl thienyl 25 Phenyl H H H—CH₂—C(O)—NH- NH N —CH₂ —Cl (1-adamantyl) 26 Structure (b) H H H—CH₂—C(O)- N-phenyl N —CH₂ —Br phenyl 27 Structure (b) H H H—CH₂—C(O)-(4- N-(cyclohexyl) N —CH₂ —Br nitro-thien-2-yl) 28 CyclohexylH H H —CH₂—C(O)-(4- NH N —CH₂—CH₂— —Br nitro-thien-2-yl) 29 Phenyl H H H—CH₂—C(O)-2- N-phenyl N —CH₂—CH₂— —Cl thienyl 30 Phenyl H H H—CH₂—C(O)-(4- N-phenyl N —CH₂ —Br nitro-thien-2-yl) 31 Phenyl H H H—CH₂—C(O)- NH N —CH₂—O— —Cl NH(Cyclopropyl) 32 Structure (b) H H H—CH₂—C(O)- N-(cyclohexyl) N —CH₂ —Cl NH(Cyclopropyl) 33 Phenyl H H H—CH₂—C(O)-(5- NH N —CH₂—O— —Br chloro-thien-2-yl) 34 Phenyl H H H—CH₂—C(O)- N-phenyl N —CH₂—O— —Cl phenyl 35 Structure (b) H H H—CH₂—C(O)-2- N-(cyclohexyl) N —CH₂ —Cl thienyl 36 Phenyl H H H—CH₂—C(O)- N-phenyl N —CH₂—O— —Cl NH(Cyclopropyl) 37 Cyclohexyl H H H—CH₂—C(O)-2- N-phenyl N —CH₂—CH₂— —Cl thienyl 38 Phenyl H H H—CH₂—C(O)-2- N-(cyclohexyl) N —CH₂—O— —Cl thienyl  39* Phenyl H H H NullNH N —CH₂ Null  40* Phenyl H H H Null NH N —CH₂—O— Null 41 Structure (b)H H H Null NH N —CH₂ Null 42 Cyclohexyl H H H Null NH N —CH₂—CH₂— Null43 Phenyl H H H —CH₂—C(O)-2- NH N —CH₂—O— —Br naphthyl 44 Phenyl H H H—CH₂-phenyl NH N —CH₂ —Cl 45 1-Naphthyl H H H —CH₂—C(O)-2- NH N —CH₂ —Clthienyl 46 2-Theinyl H H H —CH₂C(O)-2- NH N —CH₂ —Cl phenyl 47 Phenyl HH H —CH₂—C(O)-5- NH N —CH₂—CH₂— —Cl methyl-thien-2-yl) 48 Phenyl H H H—CH₂—C(O)-(5- NH N —CH₂—CH₂—CH₂—O— —Cl methyl-thien-2-yl) 49 Phenyl H HH Isopropyl NH N —CH₂ —Br 50 Phenyl H H H —CH₂—C(O)-(5- NH N —CH₂—S —Clmethyl-thien-2-yl) 51 1-methyl- H H H —CH₂—C(O)-2- NH N —CH₂ —Clindole-3-yl thienyl 52 H H H H —CH₂—C(O)-2- NH N —CH₂ —Br naphthyl 53Phenyl H H H —CH₂—C(O)—NH- NH N —CH₂ —Cl (3,4-ethylenedioxy- phenyl) 54Phenyl H 5-Br H —CH₂C(O)-2- NH N Null —Cl thienyl 55 Phenyl H Benzene—CH₂C(O)-2- NH N Null —Cl ring fused thienyl at 5,6 position 56 Phenyl HBenzene null NH N Null —Cl ring fused at 5,6 position*Isolated in the form of HCl salt.

According to the embodiment of the present invention, the presentcompounds are used for the treatment of diabetic complications, andaging related vascular and neurovascular complications including kidneydisease, nerve damage, atherosclerosis, retinopathy, inflamatorydisorders, immunological disorders, oxidative stress, dermatological &cosmetic indications and colouration of teeth occurring due to thehigher levels of preformed AGE. The increased levels of preformed AGEcan be brought under control by breaking/inhibiting the AGE productsusing compounds mentioned in the invention.

The novel compounds of the invention of general formula I can besynthesized. One way to prepare the compounds is by reactingα-substituted/unsubstituted acetyl pyridines with alkyl/aryl esters inthe presence of a suitable base. Further, it is cyclized by varioussynthetic methods. If required, quarternization can be done withappropriate reagent by refluxing in alcoholic solvents like, methanol,ethanol, propanol, etc and high boiling solvents like toluene, xylene orDMF for 6-48 hrs. to give the desired compounds.

The examples of substituted pyridine derivatives which can be used forpreparation of specific compounds of the invention are given below:

-   1. N,N′-bis(nicotinyl)hydrazine-   2. 3-[(2-pyridyl)hydrazinocarbonyl]pyridine-   3. 3-[2-methanesulfonyl)hydrazinocarbonyl]pyridine-   4. 3-[(2-benzoyloxy)ethylaminocarbonyl]pyridine-   5. 3-[(2-phenylsulfonyl)hydrazinocarbonyl]pyridine-   6. 3-[(2-acetoxy)ethyloxycarbonyl]pyridine-   7. 3-[(2-benzoyloxy)ethyloxycarbonyl]pyridine-   8. 3-[(2-methoxy)ethyloxycarbonyl]pyridine-   9. 3-[(2-phenylaminocarbonyl)hydrazinocarbonyl]pyridine-   10. 3-[(2-acetoxy)ethylaminocarbonyl]pyridine-   11. 3-[(2-(4-methylphenyl sulfonylhydrazinocarbonyl))]pyridine-   12. 3-[(2-benzoyl)-hydrazino carbonyl]pyridine-   13. 3-[(2-phenylmethane sulfonyl)hydrazino carbonyl]pyridine-   14. 3-[(2-(3-cyclohexylpropanoyl)hydrazino carbonyl]pyridine-   15. 3-[(2-methoxy)ethylaminocarbonyl]pyridine-   16. 3-[1-oxo-1-(2-methoxycarbonyl)pyridyl]hydrazino pyridine

The examples of quaternizing agents, which may be used in the reaction,are given below:

1. 2-bromoacetyl thiophene

2. 2-chloroacetyl thiopene

3. phenacylbromide

4. phenacylchloride

5. 2,4-dichloropheanacylbromide

6. N-phenyl chloroacetamide

7. N-cyclopropyl chloroacetamide

8. ethylbromoacetate

9. bromo acetylfuran

10. N-isopropylchloroacetamide

11. N-chloroacetyl-2-pyrrolidinone

12. chloroacetic acid

In-Vitro Screening for AGE-Breaking Activity

EXAMPLE 1A

The in vitro AGE formation, studied in the laboratory, by incubatingreducing sugar glucose, with protein bovine serum albumin, resulted inbrowning of solution and increase in the fluorescence. Fluorescence wasused as the criteria to monitor the increased AGE formation.

Materials:

Bovine serum albumin (fraction V) (BSA)

Glucose, analytical grade

Phosphate buffered saline (PBS)

Equipment:

Microplate ELISA Reader—Spectramax Plus (Molecular Devices, USA)

Microplate washer, (Bio-Tec Instruments, USA)

pH meter

Methods of experiment: Elisa (Enzyme Linked Immunosorbent Assay)

160 mg/ml of protein, bovine serum albumin, BSA and 1.6M glucose sugarwere dissolved in phosphate buffered saline, PBS. Sodium azide was addedat 0.02% concentration as a preservative. The solution was filteredasceptically through a 0.22 μM filter and kept for aging at 37° C. for16 weeks. After 16 weeks the solution was dialyzed against PBS,aliquoted and stored at −20° C.

To determine the AGE breaking activity, 10 μg/ml of the 16 weeks AGE-BSAwas incubated with different concentrations of the test compounds at 37°C. for 24 hours and AGE breaking activity of the test compounds by ELISAwas determined.

ELISA was performed as follows:

1. Different concentrations of 16 weeks AGE-BSA were coated on amicrotitre plate as standard. Each concentration is coated intriplicates.

2. The test samples were coated on microtitre plate at a concentrationof 5 ng. to 20 ng per well in triplicates.

3. The plate was incubated at 37° C. for one hour.

4. After incubation the plate was washed with PBST (PBS with 0.05% Tween20).

5. Blocking with 5% skimmed milk in PBS at 37° C. for one hour was done.

6. The plate was washed with PBST.

7. Primary antibody against AGE-BSA was added and the plate is incubatedat 37° C. for one hour.

8. The plate was washed with PBST.

9. Secondary antibody anti rabbit HRPO (Horse-Radish Per Oxidase)conjugate was added and the plate is incubated at 37° C. for one hour.

10. The plate was washed with PBST.

11. Colour development with OPD (orthophenylenediamine dihydrochloride)and hydrogen peroxide was done.

12. OD (optical density) at (450 nm reading-620 nm reading) was measuredafter incubation at 37° C. for 15 minutes with Microplate ELISA Reader.

The breaker activity of the compounds were determined by the followingformula:${\%\quad{Breaker}\quad{activity}} = \frac{{{OD}_{450 - 620}{Control}} - {{OD}_{450 - 620}{Test}}}{{OD}_{450 - 620}{Control}}$

OD₄₅₀₋₆₂₀Control=Absorbance of 20 ng AGE-BSA after incubation at 37° C.for 24 hours without test compound.

OD₄₅₀₋₆₂₀Test=Absorbance of 20 ng AGE-BSA after incubation at 37° C. for24 hours with required concentration of test compound.

EXAMPLE 1B

Gel Permeation Chromatography Based Method

Gel Permeation Chromatography based method was used to determine AGEbreaking activities of the compounds.

Principle:

Separation by Gel Permeation Chromatography (GPC) depends on differencesin the size, more precisely the hydrodynamic volume, of the proteins ina sample. The larger molecules do not enter the pores of the columnparticles and elute in void volume of the column (V₀). The pores of acolumn particle are differentially accessible to smaller particles,depending on their size. This volume of the column is called (V_(i)).The total accessible volume (V_(t)) is the sum of the volume outside theparticles (V₀) and the volume accessible inside the particles (V_(i)):V _(t) =V ₀ +V _(i)

Therefore, in a typical Gel Permeation Chromatography (GPC) run, highmolecular weight molecules elute at a lower retention time whereas lowermolecular weight molecules are retained for longer time. For the purposeof quantification, the area under the curve for the respective moleculeis recorded. The same principle has been applied in the in vitroscreening of the molecules of instant invention. Highly cross-linkedAdvanced Glycosylated Endproducts (AGE) were prepared in vitro byincubating Bovine Serum Albumin (BSA) with glucose for a period of 16weeks. The molecular weight of BSA and AGE-BSA differs significantly ona GPC column and hence, there is a very good resolution between the two.The reduction in the area of AGE-BSA incubated in the presence of AGEbreaker as compared to that of control AGE BSA (incubated in absence ofAGE breaker) gives an estimate of the AGE breaker activity of the drug.In order to check the non-specific activity of the molecule, a similarexperiment was repeated with BSA as well.

Methodology:

A known concentration of 16-week AGE-BSA was incubated with and withouta predetermined concentration of the drug at 37° C. for 24 hours inclean transparent glass test tubes. The solution without drug served asthe control and the solution containing the drug was treated as the testsample.

Gel permeation chromatography was performed on equal volumes of controlAGE-BSA preparation and solution of AGE-BSA treated with drug. Averageareas of the two chromatograms were calculated.

Two major peaks were observed in the chromatogram of the control andtreated AGE-BSA samples:

Peak I=High molecular weight peak

Peak II=Low molecular weight peak

Peak I+Peak II=Total AGE-BSA

Calculations:${\%\quad{Breakage}\quad{in}\quad{Peak}\quad I} = {100 - {\frac{\left( {{Average}\quad{area}\quad{of}\quad{Peak}\quad I\quad{in}\quad{treated}\quad{sample}} \right)}{\left( {{Average}\quad{area}\quad{of}\quad{Peak}\quad I\quad{in}\quad{control}\quad{sample}} \right)} \times 100}}$${\%\quad{Breakage}\quad{in}\quad{Peak}\quad{II}} = {100 - {\frac{\left( {{Average}\quad{area}\quad{of}\quad{Peak}\quad{II}\quad{in}\quad{treated}\quad{sample}} \right)}{\left( {{Average}\quad{area}\quad{of}\quad{Peak}\quad{II}\quad{in}\quad{control}\quad{sample}} \right)} \times 100}}$${\%\quad{Breakage}\quad{Total}} = {100 - {\frac{\left( {{{Average}\quad{area}\quad{of}\quad{peak}\quad I} + {{Peak}\quad{II}\quad{in}\quad{treated}\quad{sample}}} \right)}{\left( {{{Average}\quad{area}\quad{of}\quad{peak}\quad I} + {{Peak}\quad{II}\quad{in}\quad{control}\quad{sample}}} \right)} \times 100}}$

Using representative compounds, the % AGE breaking activity wascalculated and results recorded in Table 2 given below: TABLE 2 SampleConcentration (Compound No.) (mM) % Breakage Compound 7  1.0 51.72Compound 8  5 85.31 Compound 11 5.0 76.84 Compound 12 10 89.23 Compound13 10 81.05 Compound 14 10 58.14 Compound 15 10 80.03 Compound 16 1095.51 Compound 17 10 52.27 Compound 18 5.0 52.97 Compound 19 10 91.22Compound 21 10 93.43 Compound 22 10 100.00 Compound 23 10 53.29 Compound24 10 97.72 Compound 25 5 98.59 Compound 26 10 42.37 Compound 27 1086.98 Compound 31 10 45.72 Compound 34 10 100.0 Compound 35 10 66.66Compound 37 10 85.45 Compound 40 10 66.06

Thus, compounds 7, 8, 11-19, 21-25, 27, 34, 35, 37 and 40 exhibits verygood AGE breaking activity, of which the potency of compounds 8, 11-13,15, 16, 19, 21, 22, 24, 25, 27, 34 and 37 are significantly of highorder.

AGE Inhibiting Activity of the Compounds

Further in view of the ability of the compounds of the instant inventionto prevent the onset of AGE formation by the inhibitory action nowdiscovered, development of pathology condition caused by AGE could beprevented or reduced. The dual activities of the compounds as AGEbreaker and also as AGE inhibitor make them even more useful for thedisease related to aging and diabetic complications, kidney diseases,nerve damage, retinopathy, neuropathy, endothelial dysfunction,atherosclerosis, micro angiopathy, browning that occurs in the oralcavity like browning of tooth, alzheimer, artirial compliance anddistensibility, restenosis, abnormal tissue hindrance in peritonealdialysis, erectile dysfunction and other dysfunction wherein the load ofAGE on the cell is very crucial. In fact a triple action of thecompounds (a) AGE breaker (b) AGE inhibitor (c) Free radical scavengercan be effectively utilized for reversal of prevention of severalpathological conditions as well as reversal and prevention of cosmeticaspects of aging.

EXAMPLE 1C

Test for AGE Inhibiting Activity.

The following method was used to determine the inhibitory effect of thetest compounds

The following method was used to determine the inhibitory effect of thetest compounds on Maillard reaction in-vitro. This method is adoptedfrom U.S. Pat. No. 5,514,676 and European Patent No. 0 339 496 A2.

A solution of Bovine Serum Albumin (BSA), ribose and test compound wasprepared in Phosphate Buffer Saline (PBS, pH 7.4) so as to have finalconcentration of BSA and ribose at 10 mg/ml and 500 mM respectively.Addition of compound was done in aseptic conditions. Sodium azide(0.02%) was also added in this solution in order to prevent microbialgrowth. A separate tube containing BSA, ribose and sodium azide in thesame concentration and buffer as above, but without any test compound,was also incubated as positive control. After incubation at 37° C. for 7days, 40 micro litre sample from each tube was removed and diluted withPBS to have final concentration of BSA at 1 mg/ml. The fluorescence ofall the samples was measured at Excitation Maximum of 355 nM and theEmission Maximum of 460 nM using f-MAX Fluorimeter (Molecular Device,USA). In order to study the effect of test compound on fluorescence,freshly prepared compound solution was mixed with previously incubatedpositive control (i.e. BSA+ribose), so as to achieve same concentrationof all the components as that of test samples.

The percent inhibition of test compound was measured as follows:${\%\quad{Inhibition}} = {\frac{{F\quad 4} - {F\quad 3}}{F\quad 4} \times 100}$

Where F3=Fluorescence of BSA+ribose+compound, F4 is fluorescence ofincubated (BSA+ribose)+freshly added test compound.

The representative compounds of general formula (I) have been tested forthe activity as AGE inhibitor and the results recorded in Table 3 givenbelow: TABLE 3 % Inhibition Compound No. Concentration (Day 7) Compound6  10 mM 66 Compound 10 2.5 mM 75 Compound 11 1.25 mM 32.9 Compound 1310 mM 57 Compound 17 2.5 mM 57.43 Compound 18 5 mM 79 Compound 19 5 mM64.23 Compound 22 2.5 mM 51 Compound 24 5 mM 82.5 Compound 26 5 mM 61.45Compound 29 5 mM 55.22 Compound 34 5 mM 60 Compound 35 10 mM 73.8AGE Breakers:

As shown in Table 2, the compounds of the present invention are usefulfor breaking AGE. Hence, the compounds of the present invention can beused as a medicament in the treatment of diabetic complications andaging-related diseases, caused by accumulation of AGE. Also, thesecompounds can inhibit accumulation of AGE by breaking AGE, they can beused as a medicament for controlling and reducing the aggravation ofdisease conditions such as diabetes and aging related complicationscaused by accumulation of AGE.

The increased burden of AGE in any given tissue is likely to result intoa pathological condition, and by different mechanisms thereafter maylead the various disease conditions Thus, reducing the tissue burden ofAGE the compounds of the instant invention can reverse these conditions,and the prevention of AGE accumulation up to a critical mass may preventthe condition from occurring in the first place. Indeed, in chronicdiabetes and in old age there is a gradual accumulation of AGE over aperiod of years (Yong Ming Li et al., 1996; Brownlee, 1995). Thecomplications associated with such mammals occur as the tissue burden ofAGE increases over a period of time. The increase in tissue burden ofAGE over time could be prevented in newly diagnosed patients byadministering AGE breaker or inhibitor compounds sufficiently early.This method would prevent and/or delay the development of complicationslisted above in these patients.

AGE Inhibitors:

As shown in Table 3, the compounds of the present invention are alsouseful for inhibiting AGE.

Thus, can be used as a medicament in the treatment of diabeticcomplications and aging-related diseases caused by accumulation of AGE,as these compounds can inhibit the formation of AGE. Furthermore, thecompounds can inhibit accumulation of AGE by inhibiting formation of AGEand they can be used as a medicament for preventing the diseases such asdiabetes and aging related complications caused by accumulation of AGE.

Hence, the conditions listed bellow arising due to formation of AGE canbe prevented or treated by the compounds of General formula (I) for tworeasons: firstly due to their AGE breaking activity and secondly due totheir AGE inhibiting activity. In fact, both the biological activitiescontribute to control the following disease conditions:

1. vascular and neuro-vascular complications,

2. nephrological disorder,

3. neurological disorder,

4. atherosclerosis,

5. retinal disorder,

6. dermatological disorder,

7. non-enzymatic browning of oral cavity,

8. endothelial or other organ dysfunction,

9. growth impairment,

10. inflammatory disorder,

11. immunological disorder,

12. oxidative stress,

13. aging and diabetic complication,

14. alzheimer disease,

15. restenosis, abnormal tissue hindrance in peritoneal dialysis,

16. abnormal tissue hindrance in peritoneal dialysis and

17. erectile dysfunction.

EXAMPLE 1D

Free Radical Scavenging Activity:

This method measures the relative ability of free radical scavengingsubstances to scavenge the ABTS^(.+) i.e. 2,2-Azino-bis-(3-ethyl benzothiazoline-6-sulfonate) radical cation as compared to a standard amountof standard or free radical scavengers antioxidants. Incubation of ABTSwith Peroxidase (metmyoglobin) and hydrogen peroxide results in theproduction of radical cation ABTS^(.+). This species is blue-green incolour and can be detected at 730 nm. Antioxidants or free radicalscavengers in the added sample that causes suppression of the color to adegree that is proportional to their concentration.

Protocol:

Preparation of Buffer Solutions:

-   -   a. Phosphate Citrate Buffer (pH 5.0): 48.5 ml of 0.1M citric        acid with sufficient 0.2M disodium hydrogen phosphate to produce        100 ml.    -   b. Phosphate Buffer Saline (PBS): Dissolve 40.0 g of NaCl, 1.0 g        of KCl, 1.0 g of KH₂PO₄ and 3.05 g of Na₂HPO₄ in 1 litre milli-Q        water. Dilute 200 ml of above solution to 1 litre with milli-Q        water (pH 7.4-7.6).

Preparation of ABTS Stock Solution (2 mM):

-   -   1 tablet (10 mg) was dissolved in phosphate citrate buffer (pH        5.0) to give a 2 mM solution.

Preparation of Horse Radish Peroxidase Working Solution:

-   -   0.1 mg was dissolved in 10 ml of phosphate buffer saline, 1 ml        of this solution was diluted to 100 ml with PBS.

Preparation of Hydrogen Peroxide (1.08 mM) Solution:

-   -   12 μl of Hydrogen Peroxide (30% w/v) was diluted to 100 ml with        PBS.

Preparation of Drug Solutions:

-   -   0.1 mM of stock solution of the drug was prepared which was        serially diluted in PBS to get 0.05 mM, 0.025 mM and 0.0125 mM        solutions.

Preparation of ABTS Radical Stock Solution:

-   -   To 2 ml of ABTS stock solution, 1 ml of horseradish Peroxidase        working solution was added.    -   As soon as 2 ml of Hydrogen peroxide solution was added to the        above solution, blue-green colour of the ABTS radicals appeared.        This solution was incubated at 30° C. for 30 min in order to        ensure the completion reaction. Make up the volume to 10 ml with        PBS.

Preparation of Control Solution:

-   -   900 μL of ABTS radical stock solution were added to an eppendorf        tube. To it were added 100 μl of PBS solution.

Preparation of Test Solution:

-   -   900 μl of ABTS radical stock solutions were added to different        eppendorf tubes. To it were added 100 μl of various        concentrations of drug solution.

Measurement of Absorbance (O.D):

-   -   The absorbance of control and test samples was recorded        immediately at 730 nm taking PBS as blank.

Calculation:

The percent antioxidant activity was calculated according to theformula:% Antioxidant activity=100−[O.D of test sample/O.D of control×100]

The results are tabulated in Table 4 below. TABLE 4 Relative FreeRadical Scavenging Activity (%) on ABTS Compound No. 12.5 μM 25.0 μM50.0 μM 100.0 μM Compound 6  21.99 40.56 61.68 81.04 Compound 8  22.2238.18 67.14 99.71 Compound 10 41.01 72.97 85.75 87.04 Compound 11 26.7845.74 70.61 86.46 Compound 12 22.34 40.97 71.47 84.62 Compound 13 23.5841.78 64.01 82.54 Compound 17 28.34 54.43 83.56 94.81 Compound 18 28.6553.8 84.41 95.32 Compound 19 8.37 19.42 37.62 55.18 Compound 20 6.159.06 34.31 57.75 Compound 22 22.52 29.52 30.31 31.40 Compound 24 43.6674.64 83.24 00.12 Compound 26 21.18 34.22 41.66 75.27 Compound 27 16.1627.12 39.05 51.04 Compound 29 31.82 46.84 58.84 55.22 Compound 34 13.219.08 26.39 29.40 Compound 35 28.27 39.78 58.34 74.36 Compound 37 21.7937.92 41.95 39.46 Compound 38 27.70 44.78 61.98 66.92

It is thus found that the compounds of general formula (I) as definedabove are capable scavenging free radical, apart from inhibiting AGE andAGE breaker activities.

Discussion of the Test Results on Free Radical Scavaging Activity:

(i) For Cosmetic Application

Apart from the AGE breaking and free radical scavenging activity of thecompounds of the invention their potential to inhibit AGE make themideal for different cosmetic applications as discussed above.

The compounds of present invention have thus demonstrated capability ofbreaking AGE cross links formed in proteins. The compounds alsodemonstrated the capability of quenching free radicals, which can causeirreversible damage to proteins nucleic acids, etc. The ability toreverse the formation of Advanced Glycation End products (in skinsupport protein, like collagen and hair proteins like keratin) inconjunction with free radical quenching, carries with it significantimplications and make them useful in cosmetic applications.

The compounds of present invention improves the aesthetic appearance ofskin by arresting the complications of skin at more than one crucialstages. It breaks the preformed Advanced Glycation End products (AGE)formed in skin's support proteins and delays intrinsic aging (C.Jeanmaire et. al., British Journal of Dermatology 2001:145:10-18). Thecompounds of present invention also quenches the free radicals generatedby UV exposure, pollutants etc, in the skin thereby prevents extrinsicor photoaging. The free radical quenching will also prevent theirreversible damage caused to proteins and nucleic acid. Moreover, byvirtue of free radical quenching, these compounds will reduce the loadof free radicals generated by Performed AGE's. The reduction inoxidative stress will in turn reduce the formation of reactiveintermediates involved in Amadori Product formation.

The glycation of proteins is a universal phenomenon, well known at theskin level. However, this phenomenon can also occur in other relatedparts such as the nails or the hair, particularly in the Keratin(EP1068864 A1 and EP 1110539A1).

The glycation of the dermal proteins, particularly the collagen, leadsto adverse cosmetic effects for e.g. consequences that damage the skin,the same consequences can be expected as a result of glycation ofproteins in skin related parts, such as the nails and/or the hair, andin all the protein system.

The present invention discloses the molecules with ability to break theprotein cross linking. In addition, these molecules have shown to havefree radical scavenging (anti-oxidant) activity and thus useful inseveral disease conditions where oxidative stress plays vital role inthe pathogenesis besides their cosmetic applications as discussed above.

Thus, the compounds of the instant invention are effective for at leastone of the following applications:

a) reversal and prevention of wrinkles,

b) reversal and prevention of fine lines,

c) promotion of epidermal growth,

d) photo protection of skin,

e) reversal and prevention of skin discoloration,

f) reversal and prevention of age spots,

g) conditioning and prevention of dry spot,

h) reversal and prevention of stretch marks,

i) reversal and prevention of blemishes,

j) skin care and conditioning,

k) reversal and prevention of senile xerosis,

l) conditioning and prevention of sun burns,

m) preventing and reversing the loss of collagen,

n) improving skin texture,

o) improving skin tone,

p) enhancing of skin thickness,

q) decreasing pore size,

r) restoring skin luster,

s) minimising signs of fatigue,

t) reducing acne,

u) treatment of Telangiectasia and

v) improving aesthetic appearance of hair and nails.

i) For Non-Cosmetic Application

Apart from the use of the compounds of General Formula (I) for cosmeticapplications based on their AGE-breaking/AGE inhibiting and free-radicalscavenging activities, the latter activity of these compounds can beused for control of oxidative stress for effective management ofconditions.

The test compounds listed in the table above exhibit invitro freeradical scavenging (antioxidant) activity. Excessive production of freeradicals reactive oxidative species (ROS) results in oxidative stress.Therefore, these molecules would be very effective in reducing oxidativestress by their ability to trap ROS. Antioxidants (free radicalsscavengers) are reported to be effective in the management of variousdiseases linked with oxidative stress selected from the group consistingof:

1) Neurodegenerative disorders

-   -   (a) Alzheimer's Disease    -   (b) Parkinson's Disease    -   (c) Huntington's Disease    -   (d) Motor Neuron Disease    -   (e) Prion Disease

2) Diabetes and Diabetic Vascular Complications

3) Intestinal Diseases

-   -   (a) Intestinal Ischemia    -   (b) Radiation Enteritis    -   (c) Inflammatory Bowel Disease    -   (d) Gastric and Colorectal Cancers

4) Liver Diseases

-   -   (a) Alcoholic Liver Disease    -   (b) Chronic Hepatitis C

5) Cancers

-   -   (a) Lung Cancer    -   (b) Colorectal Cancer    -   (c) Cervical Cancer    -   (d) Breast Cancer    -   (e) Malignant Melanoma

6) Cardiac Diseases

-   -   (a) Atherosclerosis    -   (b) Myocardial Infarction    -   (c) Ischemic Stroke    -   (d) Endothelial dysfunction

7) Opthalmic Disorders

-   -   (a) Cataract formation    -   (b) Macular degeneration

8) HIV Disease

9) Respiratory Diseases

-   -   (a) Chronic Obstructive Pulmonary Diseases (COPD)    -   (b) Asthma

10) Renal Diseases

-   -   (a) Glomerulonephritis    -   (b) Acute Renal failure        Preparation of the Compounds of the Present Invention

One possible non limiting method for preparing compounds of the presentinvention is given below:

The compounds of the present invention can be prepared according to thefollowing steps

Step-1: Formation of 1,3 diketo compound

Step-2: Cyclization Reaction

Step-3: Quaternization Reaction

The following examples give method of preparation of the specificcompounds according to the invention as listed in Table 1 above.

Step-1: Formation of 1,3 diketo Compound

Method 1

1,3 Diketo compound can be prepared by reactingunsubstituted/substituted acetyl pyridines with alkyl/aryl esters in asuitable base

4-(3,5-dimethyl-pyrazol-1-yl)-1-pyridin-3-yl-butane-1,3-dione

To a suspension of potassium tertiary butoxide (16.5 gm. 0.147 mole) indry THF i.e. Tetrahydro furan (150 ml) a mixture of 3-acetyl pyridine(18 gm., 0.148 mole) and ethyl-3,5-dimethylpyrazolyl acetate diluted inTHF (100 ml) was added at 5-10° C. under nitrogen atmosphere. Reactionmixture was then stirred at room temperature. (30⁰C) for 6 hour. Thenreaction mixture was poured into ice cold water with and PH was adjustedto ˜4.0 with acetic acid and extracted with ethyl acetate (4×250 ml).Combined organic layer was washed with saturated aqueous sodium chloridesolution and finally organic layer was washed With water and dried oversodium sulphate. Ethyl acetate was concentrated u/v at 50⁰C to yieldcrude product. Further tiluration with spatula in di ethyl ether yield asolid product. Separated solid was filtered and dried to yield requiredproduct.

Yield: 12.0 gm

¹H NMR (DMSO-d6 400 MHz) δ: 8.95 (1H,s), 8.75-8.73 (1H,d), 8.11-8.08(1H,m), 7.42-7.39 (1H,m), 5.95(1H,s), 5.78, (1H,s), 4.89(2H,s),2.28(3H,s), 2.19(3H,s).

MASS (m/z): 258, 259

IR (KBr cm⁻¹): 2924, 1621, 1557, 1455

Method 2

Alternatively, 1,3 Diketo compound can be prepared by reactingunsubstituted/substituted aryl esters with unsubstituted/substitutedaryl methyl ketone in a suitable base

Preparation of 1-Phenyl-3-quinoline-3-yl-propane-1,3-dione

A solution of ethyl-3-quinolinate (0.50 gm, 0.0025 mole) andacetophenone (0.30 gm, 0.0025 mole) was added to an ice-cold suspensionof potassium tertiary butoxide in THF (5.0 ml). The reaction mixture wasstirred at room temp. for 2 hours, acidified with a dilute acetic acid(10%).The resulting solid was filtered, air dried and recrystallisedfrom boiling ethyl acetate to yield the desired product as a pale yellowcolour solid.

Yield: 0.20 gm.

¹HNMR (DMSO-d₆400 MHz) δ: 9.58 (1H,s), 9.23 (1H,s), 8.25-8.13 (4H, m),7.94 (1H, t), 7.77-7.62 (5H, m)

MASS (m/z): 272

Step-2: Cyclization Reaction

3-[3{(3,5-dimethylpyrazol-1-yl methyl)-1-phenyl}pyrazol-5-yl]pyridine

To a stirred cold solution of4-(3,5-dimethyl-pyrazol-1-yl)-1-pyridin-3-yl-butane-1,3-dione (0.8 gm.,0.003 mole) in methanol (30 ml) phenyl hydrazine (0.6 gm., 0.005 mole)in methanol (10 ml) was added slowly. Reaction mixture was stirred atroom temperature (30⁰C) For 3 hours and this was concentrated underreduce pressure to yield crude oily product. The crude-product waspurified over silica gel column using ethylacetate:hexane (1:1) as aneluent to afford the required product as yellow colour solid.

Yield: 0.6 gm.

¹H NMR (DMSO-d6, 400 MHz) δ: 8.52-8.50(1H,d), 8.42(1H,s),7.59-7.56(1H,m), 7.45-7.34(4H,m), 7.28-7.26(2H,m), 6.57(1H,s),5.83(1H,s), 5.23(2H,s), 2.31(3H,s), 2.09(3H,s).

MASS (m/z): 330, 331, 332

3-[3-(3,5-dimethyl-pyrazol-1-yl-methyl)pyrazole-5-yl]pyridine

To a stirred cold solution of4-(3,5-dimethyl-pyrazol-1-yl)-1-pyridin-3-yl-butane-1,3-dione (2.5 gm.,0.0097 mole) in methanol (70 ml) Hydrazine hydrate (3.0 ml, 0.06 mole)was added slowly. Reaction mixture was stirred at room temperature(30⁰C) for 3 hours and concentrated under reduced pressure to get anoily material. Chilled water was added and reaction mixture scratchedwith spatula yielded a solid. Separated solid was filtered andrecrystallised with methanol to yield a desire product.

Yield: 1.35 gm.

¹H NMR (DMSO-d6 400 MHz) δ: 8.98-8.95(1H,d), 8.50-8.48(1H,d),8.11(1H,s), 7.45-7.40(1H,d), 6.66-6.61(1H,d), 5.81(1H,s),5.21-5.14(2H,d), 2.28(3H,s), 2.07(3H,s).

MASS (m/z): 254, 255

3-[3-{(3,5-dimethyl-pyrazol-1-ylmethyl)-1-cyclohexyl}pyrazole-5-yl]pyridine

To a cold solution of trifluoroacetic acid (22.2 gm., 0.20 mole),1-(t-butoxy carbonyl)cyclohexyl hydrazine (5.0 gm., 0.0236 mole) wasadded and stirred at room temperature (30⁰c) for 30 minutes. Reactionmixture was concentrated under reduced pressure to yield a crude oilyproduct. Water (10 ml) was added to crude product and neutralized withsaturated solution of sodium bicarbonate. The neutralized solution wasextracted with ethylacetate (3×75 ml). Combined organic layer was driedover sodium sulphate and concentrated under vacuum to yield a crude oilyproduct (2.50 gm.)

Further oily product (2.50 gm., 0.022 mole) dissolved in methanol (10ml) was added slowly to a solution of4-(3,5-dimethyl-pyrazol-1-yl)-1-pyridin-3-yl-butane-1,3-dione (2.0 gm.,0.0078 mole) in methanol (20 ml). Reaction mixture was stirred at roomtemperature (30⁰c) for 7 hours after that concentrated under reducedpressure to yield a brown colour oily product. Purification of crudeproduct was done over silica gel column chromatography using 25%ethylacetate in hexane as eluent to afford the required product as whitesolid.

Yield: 0.96 gm.

¹H NMR (DMSO-d₆ 400 MHz) δ: 8.65-8.63(1H,m), 7.85-7.82(1H,m),7.54-7.51(1H,m), 6.15(1H,s), 5.8(1H,s), 5.13(2H,s), 3.98(1H,m),2.27(3H,s), 2.07(3H,s), 1.91-1.85(4H,m), 1.78-1.75(2H,m),1.62-1.559(1H,m), 1.27-1.16(3H,m)

MASS (m/z): 336, 337, 338

Synthesis of 3-[3-(phenylmethyl)-isoxazol-5-yl]-pyridine

A mixture of phenylnicotinoyl acetone 0.500 g (0.0021 mol), isopropylalcohol (5 ml) and hydroxylamine free base (in 7 ml methanol) wasstirred at room temperature for 3 days (72 hrs.). The reaction mixturewas concentrated to dryness and purified by column chromatography usinga mixture of ethylacetate and hexanes (3:1). The purified compound(oxime) was dissolved in IPA (10 ml) and to it was added 2 N HCl (4drops). The reaction mixture was refluxed for 8 hrs. The reactionmixture is finally concentrated to dryness to yield the desired compoundas a pale yellow solid:

Yield: 0.216 gm.

¹H NMR (CDCl₃, 400 MHz) δ: 9.01 (1H, s), 8.69 (1H, d), 8.20 (1H, d),7.56 (m, 1H), 7.36-7.30 (m, 5H), 6.46 (1H, s), 4.11 (2H, s)

MASS (m/z): 237 (M⁺+1)

Step-3: Quaternization Reaction

Quaternization of the substituted pyridine can be done with aquaternizing reagent in an alcoholic and/or high boiling solvent underreflux for 6-48 hrs. to give the desired compound if required.

EXAMPLE 21-(2-Thien-2′-yl-2-oxoethyl)-3-[3-{1-(3,5-dimethylpyrazol-1-yl)methyl}pyrazol-5-yl]pyridiniumbromide. (Compound 4)

To a suspension of3-[3-(3,5-dimethyl-pyrazol-1-yl-methyl)pyrazole-5-yl]pyridine (0.5 gm.,0.002 mole) in IPA (35 ml) α-bromo 2-acetyl thiophene (0.46 gm., 0.0026mole) was added. Reaction mixture was refluxed for 6 hours. Further coolto room temperature (30⁰C). The solid separated was filtered andrecrystallised using methanol and ethylacetate mixture to yield therequired compound as a white solid.

Yield: 0.51 gm.

¹HNMR (DMSO-d₆, 400 MHz) δ: 13.66(1H,s), 9.49(1H,s), 9.03-9.01(1H,d),8.89-8.88(1H,d), 8.26-8.21(3H,m), 7.43-7.41(1H,t), 6.77(1H,s),6.39(2H,s), 5.84(1H,s), 5.27(2H,s), 2.27(3H,s), 2.08(3H,s),

MASS (m/z): 378, 379, 380

IR (KBr, cm⁻¹): 1676, 1638, 1591

The compounds of the invention as identified by their physio chemicaldata given in example 3-57 below have been prepared by following theabove synthetic method.

EXAMPLE 31-(2-Thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide

(Compound 1)

Yield: 51%

IR (KBr, cm⁻¹): 1656, 1637, 1572

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.44(1H,s), 9.46(1H,s), 8.98(1H,d),8.86(1H,d), 8.24 (3H,m), 7.41(1H,t), 7.34-7.30(5H,m), 6.69(1H,s),6.38(2H,s), 4.06(2H,s)

MASS (m/z): 360, 361, 362, 363

EXAMPLE 4 1-(2-Thien-2′-yl-2-oxoethyl)-3-[(5-phenylmethyl)oxazol-3-ylpyridinium bromide

(Compound 2)

Yield: 36%

IR (KBr, cm): 1747, 1671, 1456

¹HNMR (DMSO-d₆, 400 MHz) δ: 9.65 (1H, s), 9.12-9.08 (2H, m) 8.39 (1H, t)8.26-8.23 (2H, m), 7.42 (1H, m) 7.38 0 7.33 (5H, m), 7.23 (1H, s) 6.40(2H, s), 4.15 (2H, s)

MASS (m/z): 361, 362, 363

EXAMPLE 51-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(2-thien-2′-yl)-2-oxoethylpyridinium-4-thio}methyl-pyrazol-5-yl]pyridinium dibromide

(Compound 3)

Yield: 71%

IR (KBr, cm⁻¹) 1666, 1500, 1451

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.81(1H,s), 9.54(1H,s), 9.03-9.01(1H,d),8.93-8.91(1H,d), 8.71-8.69(2H,d), 8.30-8.13(7H,m), 7.44-7.39(2H,m),7.09(1H,s), 6.42(2H,s), 6.21(2H,s), 4.84(2H,s)

MASS (m/z): 517, 518, 519, 520

EXAMPLE 61-(2-Thien-2′-yl-2-oxoethyl)-3-[{3-phenylmethyl}-1-{2-pyridyl}-pyrazol-5-yl]-pyridiniumbromide

(Compound 5)

Yield: 22%

IR (KBr, cm⁻¹): 1671, 1585, 1550

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.24(1H,s), 8.96-8.95(1H,d),8.24-8.21(2H,m), 8.19-8.18(1H,d), 8.15-8.14(1H,d), 8.07-8.02(1H,m),7.97-7.95(1H,d), 7.41-7.31(6H,m), 7.25-7.22(1H,m), 6.76(1H,s),6.32(2H,s), 4.08(2H,s)

MASS (m/z): 437, 438, 440

EXAMPLE 71-(2-Thien-2′-yl-2-oxoethyl)-3-[3{(3,5-dimethylpyrazol-1-yl)methyl-1-(2-pyridyl)}pyrazol-5-yl]pyridiniumbromide

(Compound 6)

Yield: 310%

IR (KBr, cm⁻¹): 3418, 3069, 2929, 1670, 1507, 1470

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.25(1H,s), 8.97-8.95(1H,d),8.61-8.59(1H,d), 8.24-8.16(4H,m), 8.09-8.05(1H,m), 7.94-7.92(1H,d),7.42-7.39(2H,m), 6.72(1H,s), 6.33(2H,s), 5.85(1H,s), 5.31(2H,s),2.33(3H,s), 2.08(3H,s)

MASS (m/z): 455, 456, 457, 458

EXAMPLE 81-[2-(Cyclopropylamino)-2-oxoethyl]3-[3-{(3,5-dimethylpyrazol-1-yl)methyl}-pyrazol-5-yl]-pyridiniumbromide

(Compound 7)

Yield: 59%

IR (KBr, cm⁻¹): 3373, 3064, 1667, 1577

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.69(1H,s), 9.41(1H,s), 8.95(1H,d),8.55(1H,d), 8.54(1H,d), 8.16(1H,t), 6.80(1H,s), 5.84(1H,s), 5.39(2H,s),5.26(2H,s), 3.89-3.82(1H,m), 2.27(3H,s), 2.08(3H,s), 1.12(4H,d)

MASS (m/z): 353, 354, 355

EXAMPLE 91-{2-(4-Nitro-2-thienyl)-2-oxoethyl}-3-[3{(3,5-dimethylpyrazol-1-yl)methyl}-pyrazol-5-yl]-pyridiniumbromide

(Compound 8)

Yield: 24%

IR (KBr, cm⁻¹):

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.70 (1H, s), 9.47 (1H,s), 9.30 (1H,s),9.03 (1H,d), 8.87-8.85 (2H,m), 8.26 (1H,t), 6.77 (1H,s), 6.42 (2H,s),5.84 (1H,s), 5.27 (2H,s), 2.27 (3H,s), 2.07 (3H,s),

MASS (m/z): 423, 424

EXAMPLE 101-(2-Cyclopropylamino-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 9)

Yield: 36%

IR (KBr, cm⁻¹): 3653, 3436, 3061, 1674, 1567, 1479

¹H NMR (DMSO-d₆,400 MHz) δ: 13.46(1H,s), 9.37(1H,s), 8.93(1H,d),8.82(1H,d), 8.72-8.71(1H,d), 8.19-8.14(1H,t), 7.36-7.23(5H,m),6.72(1H,s), 5.38(2H,s), 4.06(2H,s), 2.71-2.66(1H,m), 0.70-0.66(2H,m),0.50-0.46(2H,m)

MASS (m/z): 333, 334, 335

EXAMPLE 113,5-Bis-[1-(2-thien-2′-yl-2-oxoethyl)-pyridinium-3-yl]-pyrazoledibromide

(Compound 10)

Yield: 34%

IR (KBr, cm⁻¹): 3425, 3088, 2927, 1673, 1505, 1407.

¹H NMR (DMSO-d₆,400 MHz) δ: 9.66(2H,s), 9.09-9.02(4H,m), 8.41(2H,bs),8.27-8.26(4H,m), 7.66(1H,s), 7.45-7.43(2H,t), 6.47(4H,s)

MASS (m/z): 471, 472, 473, 474

EXAMPLE 121-(2-Thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride

(Compound 11)

Yield: 42% IR (KBr, cm⁻¹): 3302, 3029, 1672, 1503.

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.20(1H,s), 8.94-8.93(1H,d),8.24-8.20(3H,m), 8.16-8.13(1H,m), 7.50-7.31(10H,m), 7.25-7.23(1H,m),6.73(1H,s), 6.32(2H,s), 4.06(2H,s)

MASS (m/z): 436, 437, 438, 439, 440

EXAMPLE 131-(2-(5-Methyl-2-Thienyl)-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 12)

Yield: 44%

IR (KBr, cm⁻¹): 3745, 1654, 1518, 1455.

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.52(1H,s), 9.48(1H,s), 8.99-8.97(1H,d),8.90-8.88(1H,d), 8.24-8.21(1H,t), 8.04-8.03(1H,d), 7.35-7.22(5H,m),7.14-7.13(1H,d), 6.70(1H,s), 6.36(2H,s), 4.07(2H,s), 2.59(3H,s)

MASS (m/z): 374, 375, 376, 377

EXAMPLE 141-(2-Thien-2′-yl-2-oxoethyl)-3-[1-phenyl,3-{(3,5-dimethylpyrazol-1-yl)methyl)}pyrazol-5-yl]-pyridiniumchloride

(Compound 13)

Yield: 27%

IR (KBr, cm⁻¹):

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.22(1H,s), 8.95-8.93(1H,d),8.25-8.21(3H,m), 8.16-8.12(1H,m), 7.64-7.60(1H,m), 7.50-7.46(2H,m),7.42-7.36(3H,m), 6.71(1H,s), 6.33(2H,s), 5.84(1H,s), 5.28(2H,s),2.29(3H,s), 2.08(3H,s)

MASS (m/z): 454, 455, 456, 457, 458.

EXAMPLE 151-(2-Phenyl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]-pyridiniumbromide

(Compound 14)

Yield: 14%

IR (KBr, cm⁻¹): 3746, 3099, 1691, 1518.

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.44(1H,s), 9.45(1H,s), 9.01-8.99(1H,d),8.85-8.84(1H,d), 8.26-8.23(1H,t), 8.07-8.06(2H,d), 7.82-7.78(1H,t),7.69-7.65(2H,t), 7.36-7.21(5H,m), 6.68(1H,s), 6.45(2H,s), 4.07(2H,s)

MASS (m/z): 354, 355

EXAMPLE 161-(2-Cyclopropylamino-2-oxoethyl)3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride

(Compound 15)

Yield: 7%

IR (KBr, cm⁻¹): 3395, 3026, 1689, 1503.

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.15(1H,s), 8.86(1H,s), 8.71(1H,s),8.14-8.05(2H,m), 7.44-7.23(10H,m), 6.74(1H,s), 5.31(2H,s), 4.05(2H,s),2.66(1H,s), 0.68-0.67(2H,s), 0.46(2H,s).

MASS (m/z): 409, 410, 411, 412

EXAMPLE 171-(2-(4-Benzyl-1-piperidinyl)-2-oxoethyl)3-[(3-phenoxymethyl)pyrazol-5-yl]-pyridiniumbromide

(Compound 16)

Yield:

IR (KBr, cm⁻¹): 3060, 1656, 1594

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.84(1H,s), 9.45(1H,s), 8.98(1H,d),8.83(1H,d), 8.21(1H,t), 7.35-7.27(4H,m), 7.23-7.19(3H,m),7.09-7.04(3H,m), 6.98(1H,t), 5.83-5.73 (2H,m), 5.21(2H,s), 4.29(1H,d),3.75(1H,d), 3.17-3.0(1H,m), 2.69-2.63(1H,m), 2.56(2H,d),1.99-1.84(1H,m), 1.72-1.60(2H,m), 1.36-1.28(1H,m), 1.10-1.04(1H,m)

MASS (m/z): 467, 468, 469

EXAMPLE 181-(2-Phenyl-2-oxoethyl)-3-[(3-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]-pyridiniumchloride

(Compound 17)

Yield: 24% IR (KBr, cm⁻¹): 3049, 2994, 1692, 1552.

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.76(1H,s), 9.50(1H,s), 9.03-9.02(1H,d),8.90-8.88(1H,d), 8.26(1H,bs), 8.08-8.06(2H,d), 7.81-7.78(1H,m),7.68-7.65(2H,m), 6.75(1H,s), 6.49(2H,s), 5.83(1H,s), 5.26(2H,s),2.26(3H,s), 2.06(3H,s).

MASS (m/z): 372, 373, 374.

EXAMPLE 191-(2-(5-Methyl-2-thienyl)-2-oxoethyl)-3-[(3,-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]pyridiniumchloride

(Compound 18)

Yield: 34%

IR (KBr, cm⁻¹): 3322, 2923, 1659, 1552.

¹HNMR (DMSO-d₆, 400 MHz) δ: 13.71(1H,s), 9.48(1H,s), 9.01-8.99(1H,d),8.89-8.87(1H,d), 8.23(1H,bs), 8.04-8.03(1H,d), 7.13(1H,s), 6.76(1H,s),6.33(2H,s), 5.83(1H,s), 5.26(2H,s), 2.58(3H,s), 2.26(3H,s), 2.07(3H,s)

MASS (m/z): 392, 393, 394, 395

EXAMPLE 201-(2-Phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 19)

Yield: 63%

IR (KBr, cm⁻¹): 3351, 3235, 3030, 1694, 1504.

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.17(1H,s), 8.93-8.91(1H,d),8.25-8.23(1H,d), 8.17-8.14(1H,t), 8.06-8.04(2H,d), 7.81-7.78(1H,t),7.68-7.64(2H,t), 7.49-7.44(3H,m), 7.38-7.30(6H,m), 7.24-7.20(1H,m),6.72(1H,s), 6.40(2H,s), 4.05(2H,s).

MASS (m/z): 430, 431, 432

EXAMPLE 211-(2-(5-Methyl-2-thienyl)-2-oxoethyl)-3-[(3(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 20)

Yield: 30%

IR (KBr, cm⁻¹): 3072, 2920, 1658, 1519, 1450.

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.33(1H,s), 9.52(1H,s), 8.99-8.97(1H,d),8.92-8.90(1H,d), 8.26-8.22(1H,t), 8.06-8.05(1H,d), 7.14(1H,s),6.76(1H,s), 6.40(2H,s), 2.71-2.67(2H,t), 2.59(3H,s), 1.75-1.63(5H,m),1.57-1.52(2H,q), 1.24-1.16(4H,m), 0.95-0.90(2H,m).

MASS (m/z): 394, 395, 396

EXAMPLE 221-(2-Cyclopropylamino-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 21)

Yield: 39%

IR (KBr, cm⁻¹): 3174, 2923, 1682, 1548.

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.25(1H,s), 9.40(1H,s), 8.94-8.91(1H,d),8.85-8.84(1H,d), 8.60-8.58(1H,d), 8.18-8.15(1H,m), 6.79(1H,s),5.43(2H,s), 3.90-3.85(1H,m), 2.71-2.67(2H,t), 1.75-1.63(5H,m),1.58-1.52(2H,q), 1.24-1.12(8H,m), 0.96-0.88(2H,m)

MASS (m/z): 355, 356, 357.

EXAMPLE 231-(2-Phenyl-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 22)

Yield: 65%

IR (KBr, cm⁻¹): 3059, 2924, 1698, 1519.

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.26(1H,s), 9.49(1H,s), 9.00-8.98(1H,d),8.88-8.86(1H,d), 8.28-8.24(1H,m), 8.09-8.07(2H,d), 7.83-7.79(1H,t),7.70-7.66(2H,t), 6.75(1H,s), 6.50(2H,s), 2.69(2H,t), 1.75-1.61(5H,m),1.58-1.52(2H,q), 1.27-1.08(4H,m), 0.96-0.88(2H,m).

MASS (m/z): 374, 375, 376

EXAMPLE 241-(2-Cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 23)

Yield: 9%

IR (KBr, cm⁻¹): 3165, 2994, 1662, 1500, 1452.

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.11(1H,s), 9.01-9.00(1H,d),8.69-8.67(1H,d), 8.60-8.58(1H,d), 8.27-8.24(1H,m), 7.33-7.29(4H,m),7.22-7.19(1H,m), 6.38(1H,s), 5.42 (2H,s), 4.08-4.02(1H,m), 3.96(2H,s),3.91-3.85(1H,m), 1.89(4H,bs), 1.78-1.75(2H,d), 1.64-1.61(1H,d),1.41(2H,bs), 1.21-1.16(1H,m), 1.13-1.12(4H,d)

MASS (m/z): 417, 418, 419

EXAMPLE 251-(2-Thien-2′-yl-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 24)

Yield: 18%

IR (KBr, cm⁻¹): 3060, 2957, 1665, 1595, 1491.

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.82(1H,s), 9.55(1H,s), 9.06-9.04(1H,d),8.93-8.91(1H,d), 8.30-8.22(3H,m), 7.44-7.43(1H,m), 7.35-7.31(2H,m),7.08-7.05(3H,m), 7.01-6.97(1H,m), 6.43(2H,s), 5.22(2H,s)

MASS (m/z): 376, 377, 378

EXAMPLE 261-{2-(1-Adamantylamino-2-oxoethyl)}-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 25)

Yield: 27%

IR (KBr, cm⁻¹): 3060, 2908, 1679, 1554.

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.45(1H,s), 9.35(1H,s), 8.91(1H,d),8.80(1H,d), 8.20(1H,s), 8.14(1H,t), 7.35-7.31(5H,m), 6.74(1H,s),5.36(2H,s), 4.07(2H,s), 2.02-1.95(9H,m), 1.62(6H,s)

MASS (m/z): 427, 428, 429

EXAMPLE 271-(2-Phenyl-2-oxoethyl)-3-[{3-(3,5-dimethylpyrazol-1-yl)methyl)}1-phenyl-pyrazol-5-yl]pyridiniumbromide

(Compound 26)

Yield: 47%

IR (KBr, cm⁻¹): 3410, 3035, 2943, 1693, 1500.

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.19(1H,s), 8.93-8.91(1H,d),8.25-8.23(1H,d), 8.18-8.14(1H,m), 8.07-8.05(2H,m), 7.82-7.79(1H,m),7.69-7.64(2H,m), 7.53-7.47(3H,m), 7.40-7.37(2H,m), 6.71(1H,s),6.40(2H,s), 5.84-5.83(1H,s), 5.28(2H,s), 2.29(3H,s), 2.08(3H,s)

MASS (m/z): 448, 449

EXAMPLE 281-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl)-methyl)pyrazol-5-yl]pyridiniumbromide

(Compound 27)

Yield: 56%

IR (KBr, cm⁻¹): 3421, 3032, 2935, 1688, 1541.

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.30(1H,d), 9.14(1H,s), 9.04-9.02(1H,d),8.87-8.86(1H,d), 8.79-8.77(1H,d), 8.38-8.35(1H,m), 6.46(2H,s),6.36(1H,s), 5.82(1H,s), 5.18(2H,s), 4.15-4.10(1H,m), 2.25(3H,s),2.07(3H,s), 1.90-1.84(4H,m), 1.81-1.77(2H,d), 1.66-1.63(1H,d),1.38-1.19(3H,m).

MASS (m/z): 505, 506, 507

EXAMPLE 291-(2-(4-Nitro-2-thienyl)-2-oxoethyl)-3[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide

(Compound 28)

Yield: 48%

IR (KBr, cm⁻¹): 3078, 3005, 1695, 1541, 1339

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.24(1H,s), 9.48(1H,s), 9.30(1H,s),9.0(1H,d), 8.87-8.84(2H,m), 8.27(1H,t), 6.76(1H,s), 6.46(2H,s),2.69(2H,t), 1.99-1.61(5H,m), 1.58-1.52(2H,q), 1.26-1.12(4H,m),0.96-0.87(2H,m)

MASS (m/z): 425

EXAMPLE 301-(2-Thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 29)

Yield: 16%

IR (KBr, cm⁻¹): 3347, 3022, 2906, 1682, 1503

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.3(1H,s), 9.0(1H,s), 8.29-8.24(4H,m),7.6-7.3(8H,m), 7.0(3H,s), 6.97(1H,s), 6.38(2H,s), 5.2(2H,s)

MASS (m/z): 452, 453, 454

EXAMPLE 311-(2-(4-Nitro-2-thienyl)-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide

(Compound 30)

Yield: 23%

IR (KBr, cm⁻¹): 3092, 3003, 2932, 1687, 1509

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.298(1H,s), 9.16(1H,s), 8.917(1H,d),8.85-8.84(1H,m), 8.54(1H,d), 8.17-8.14(1H,m), 7.50-7.45(3H,m),7.39-7.31(6H,m), 7.25-7.22(1H,m), 6.7(1H,s), 6.357(2H,s), 4.0(2H,s)

MASS (m/z): 481, 482

EXAMPLE 321-(2-Cyclopropylamino-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 31)

Yield: 34%

IR (KBr, cm⁻¹): 3647, 3420, 3227, 2958, 1675

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.82(1H,s), 9.46(1H,s), 8.98(1H,s),8.87(1H,d), 8.77(1H,m) (1H,d), 8.207(1H,t), 7.33(2H,t), 7.1(1H,s),7.059(2H,d), 6.98(1H,t), 5.4(2H,s), 5.21(2H,s), 2.7-2.68(1H,m),0.715-0.685(2H,m), 0.55-0.50(2H,m)

MASS (m/z): 349, 350, 351

EXAMPLE 331-(2-Cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl)methyl)pyrazole-5-yl]pyridiniumchloride

(Compound 32)

Yield: 41%

IR (KBr, cm⁻¹): 3425, 3174, 2938, 1658, 1500

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.1(1H,s), 9.02(1H,d), 8.88(1H,d),8.86(1H,d), 8.273(1H,t), 6.36-6.34(1H,s), 5.8(1H,s), 5.4(2H,s),5.18(2H,s), 4.13-4.079(1H,m), 2.7-2.68(1H,m), 2.26(3H,s), 2.074(3H,s),1.99-1.75(6H,m), 1.64-1.61(1H,m), 1.34-1.31(2H,m), 1.24-1.17(1H,m),0.70-0.69(2H,m), 0.50-0.49(2H,m)

MASS (m/z): 433, 434, 435

EXAMPLE 341-(2-(5-Chloro-2-thienyl)-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide

(Compound 33)

Yield: 74%

IR (KBr, cm⁻¹): 2853, 2682, 1674, 1594

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.8(1H,s), 9.53(1H,s), 9.03(1H,d),8.89(1H,d), 8.3-8.26(1H,m), 8.16(1H,d), 7.5(1H,d), 7.33(2H,t),7.08(3H,t), 6.98(1H,t), 6.38(2H,s), 5.2(2H,s)

MASS (m/z): 410, 412, 413

EXAMPLE 351-(2-Phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 34)

Yield: 25%

IR (KBr, cm⁻¹): 3020, 2905, 1701, 1634, 1595

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.23(1H,s), 8.96(1H,d), 8.33(1H,d),8.21(1H,t), 8.07(2H,d), 7.81(1H,t), 7.68(2H,t), 7.51-7.50(3H,m),7.41(2H,d), 7.32(2H,t), 7.08-7.06(3H,m), 6.97(1H,t), 6.42(2H,s),5.21(2H,s)

MASS (m/z): 446, 447

EXAMPLE 361-(2-Thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]pyridiniumchloride

(Compound 35)

Yield: 26%

IR (KBr, cm⁻¹): 3422, 2937, 1678, 1505, 1251

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.17(1H,s), 9.05(1H,d), 8.76(1H,d),8.35(1H,t), 8.25-8.24(2H,m), 7.42(1H,t), 6.41(2H,s), 6.36(1H,s),5.85(1H,s), 5.18(2H,s), 4.13-4.10(1H,m), 2.25(3H,s), 2.06(3H,s),1.99-1.86(4H,m), 1.83-1.76(2H,m), 1.66-1.63(1H,m), 1.35-1.25(2H,m),1.22-1.16(1H,m)

MASS (m/z): 460, 461, 462

EXAMPLE 371-(2-cyclopropylamino-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide

(Compound 36)

Yield: 9%

IR (KBr, cm⁻¹): 3200, 1682, 1595

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.29(1H,s), 9.06(1H,s), 8.97(1H,d),8.21(1H,d), 8.10(1H,t), 7.48(3H,s), 7.39-7.18(5H,m), 7.14-7.07(2H,m),6.97(1H,t), 5.43(2H,s), 5.20(2H,s), 2.68-2.62(1H,m), 0.70-0.62(2H,m),0.50-0.44(2H,m).

MASS (m/z): 425, 426, 427

EXAMPLE 381-(2-Thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide

(Compound 37)

Yield: 31%

IR (KBr, cm⁻¹): 3423, 3324, 2922, 1674, 1506

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.25(1H,s), 8.90(1H,d), 8.27-8.23(3H,m),8.19-8.15(1H,m), 7.49-7.41(4H,m), 7.35(2H,d), 6.8(1H,s), 6.37(2H,s),2.69(2H,t), 1.77(2H,d), 1.69-1.55(5H,m), 1.32(1H,m), 1.26-1.12(3H,m),0.97-0.89(2H,m).

MASS (m/z): 456, 457, 458

EXAMPLE 391-(2-Thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 38)

Yield: 18%

IR (KBr, cm⁻¹): 3396, 2934, 1670, 1638, 1594

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.25(1H,s), 9.10(1H,d), 8.82(1H,d),8.39(1H,t), 8.26-8.25(2H,m), 7.43(1H,t), 7.30(2H,t), 7.04(2H,d),6.95(1H,t), 6.75(1H,s), 6.46(2H,s), 5.09(2H,s), 4.20-4.15(1H,m),1.93-1.77(6H,m), 1.67(1H,d), 1.36-1.20(3H,m).

MASS (m/z): 458, 459, 460

EXAMPLE 40 3-[(3-phenylmethyl)pyrazol-5-yl]pyridine hydrochloride

(Compound 39)

Yield: 73%

IR (KBr, cm⁻¹): 3056, 1611, 1559

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.18(1H,s), 8.73(2H,d), 7.93(1H,t),7.35-7.22(5H,m), 6.77(1H,s), 4.04(2H,s)

MASS (m/z): 236, 237

EXAMPLE 41 3-[(3-phenoxymethyl)pyrazol-5-yl]pyridine hydrochloride

(Compound 40)

Yield: 65%

IR (KBr, cm⁻¹): 3035, 1601, 1562

¹H NMR (DMSO-d₆, 400 MHz) δ: 9.25(1H,s), 8.77(2H,s), 7.97(1H,t),7.32(2H,t), 7.12(1H,s), 7.05(2H,d), 6.97(1H,t), 5.17(2H,s)

MASS (m/z): 252, 253, 254

EXAMPLE 42 3-[(3,5-Dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridine

(Compound 41)

Yield: 93%

IR (KBr, cm⁻¹): 3080, 1559

¹H NMR (DMSO-d₆, 400 MHz) δ: 13.30(1H,bs), 8.96(1H,s), 8.49(1H,s),8.11(1H,d), 7.43(1H,bs), 6.63(1H,s), 5.81(1H,s), 5.17(2H,s), 2.28(3H,s),2.07(3H,s)

MASS (m/z): 254, 255, 256

EXAMPLE 43 3-[3-(2-cyclohexylethyl)-pyrazol-5-yl]pyridine

(Compound 42)

Yield: 76%

IR (KBr, cm⁻¹):

¹H NMR (DMSO-d₆, 400 MHz) δ: 12.73(1H,s), 8.98(1H,s), 8.46(1H,s),8.11(1H,d), 7.46-7.38(1H,d), 6.57(1H,s), 2.63(2H,t), 1.75-1.60(5H,m),1.56-1.50(2H,m), 1.25-1.08(4H,m), 0.95-0.87(2H,m).

MASS (m/z): 256, 257, 258.

EXAMPLE 441-(2-Napthyl-2-oxoethyl)-3[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide

(Compound 43)

Yield: 30%

IR (KBr, cm⁻¹): 3417, 2340, 1638, 1536, 1144

¹HNMR (DMSO-d6, 400 MHz) δ: 13.8 (1H, s), 9.58 (1H, s), 9.08-9.06(1H,d), 8.95-8.93 (1H, d), 8.85 (1H, s), 8.32 (1H, t), 8.25-8.23 (1H,d), 8.18-8.16 (1H, d), 8.10-8.05 (2H, m), 7.79-7.70 (2H, m), 7.33 (2H,t), 7.10 (1H, s), 7.06-7.04 (2H, d), 6.98 (1H, t), 6.63 (2H, s), 5.23(2H, s)

MASS (m/z): 420, 421

EXAMPLE 45 1-(Phenylmethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 44)

Yield: 31%

IR (KBr, cm⁻¹): 3051, 1523, 1466

¹HNMR (DMSO-d6, 400 MHz) δ: 13.48 (1H, s), 9.63 (1H, s), 9.05-9.03 (1H,d), 8.91-8.90 (1H, d) 8.15 (1H,t) 7.55 (2H, m), 7.45-7.43 (3H, m),7.34-7.25 (5H, m) 6.79 (1H, s), 5.88 (2H, s), 4.06 (2H, s)

MASS (m/z): 326, 327, 328

EXAMPLE 461-(2-Thien-2′-yl-2-oxoethyl)-3[(3(-1-naphthyl)pyrazol-5-yl]pyridiniumchloride

(Compound 45)

Yield: 22%

IR (KBr, cm⁻¹): 3057, 1671, 1517

¹HNMR (DMSO-d6, 400 MHz) δ: 13.60 (1H, s), 9.40 (1H, s) 8.97-8.95 (1H,d), 8.86-8.85 (1H, d), 8.23-8.18 (3H, m), 8.10-8.08 (1H, d), 7.87-7.86(1H, d), 7.55-7.44 (4H, m), 7.40 (1H, t), 6.55-6.52 (1H, s), 6.40 (2H,s), 4.54 (2H, s)

MASS (m/z): 410, 411, 412

EXAMPLE 471-(2-Phenyl-2oxoethyl)-3[3(thienyl-2-yl-methyl)pyrazol-5-yl]pyridiniumchloride

(Compound 46)

Yield: 22%

IR (KBr cm⁻¹): 3068, 1691, 1519

¹HNMR (DMSO-d6, 400 MHz) δ: 13.55 (1H, s), 9.50 (1H, s), 9.01 (1H, d),8.87 (1H, d), 8.26 (1H, t) 8.07 (2H, m), 7.81 (1H, d), 7.68 (3H, t),7.40 (2H, m), 6.78 (1H, s), 6.49 (2H, s) 4.30 (2H, s)

MASS (m/z): 360, 361

EXAMPLE 481-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[3(2-phenylethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 47)

Yield: 24%

IR (KBr, cm⁻¹): 3068, 1661, 1450

¹HNMR (DMSO-d6, 400 MHz) δ: 13.33 (1H, s), 9.47 (1H, s), 8.97-8.95 (1H,d), 8.87-8.86 (1H, d), 8.26-8.22 (1H, t), 8.05-8.04 (1H, d), 7.31-7.14(6H, m), 6.78 (1H, s), 6.34 (2H, s), 2.98 (4H, s), 2.59 (3H, s)

MASS (m/z): 388, 389, 390

EXAMPLE 49 1-(2-(5-Methyl2-thienyl)-2-oxoethyl)-3-[3-(3-phenoxypropyl)pyrazol-5-yl]pyridiniumchloride

(Compound 48)

Yield: 30%

IR (KBr cm⁻¹): 3057, 1665, 1452

¹HNMR (DMSO-d₆, 400 MHz) δ: 13.34 (1H, s), 9.48 (1H, s), 8.99-8.97 (1H,d), 8.23 (1H, t), 8.05-8.04 (1H, d), 7.28 (1H, t), 7.15-7.14 (1H, d),6.94-6.92 (3H, d) 6.83 (1H, s), 6.35 (2H, s), 4.02 (2H, t), 2.86 (2H,t), 2.27 (2H, t)

MASS (m/z): 418, 419, 420

EXAMPLE 50 1-(Isopropyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide

(Compound 49)

Yield: 15%

IR (KBr, cm⁻¹): 3418, 2364, 1648

¹HNMR (DMSO-d6, 400 MHz) δ: 9.43 (1H, s), 9.09-9.07 (1H, d), 8.88-8.86(1H, d), 8.16 8.13 (1H, m), 7.36-7.14 (5H, m), 6.84 (1H, s), 4.06 (2H,s), 1.65-1.63 (6H, d)

MASS (m/z): 278, 279, 280

EXAMPLE 511-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3-phenylthiomethyl)pyrazol-5-yl]pyridiniumchloride

(Compound 50)

Yield: 31%

IR (KBr cm⁻¹): 3365, 1650, 1452

¹HNMR (DMSO-d6, 400 MHz) δ: 13.58 (1H, s), 9.46 (1H, s), 8.98-8.96 (1H,d), 8.87-8.85 (1H, d), 8.25-8.21 (1H, m), 8.04-8.03 (1H, d), 7.37-7.30(5H, m), 7.15-7.14 (1H, d), 6.88 (1H, s), 6.32 (2H, s), 4.36 (2H, s),2.59 (3H, s)

MASS (m/z): 406, 407, 408, 409

EXAMPLE 52 1-(2-Thien-2′-yl-2-oxoethyl)-3[(3-(N-methyl-indole-3-ylmethyl)pyrazol-5-l]pyridinium chloride

(Compound 51)

Yield: 20%

IR (KBr cm⁻¹): 3070, 1669, 1410

¹HNMR (DMSO-d6, 400 MHz) δ: 9.32-9.30 (1H, m), 9.00-8.92 (2H, m),8.77-8.76 (1H, d), 8.19-8.15 (2H, m), 8.10-8.07 (1H, m), 7.47-7.45 (1H,d), 7.39-7.35 (3H, m) 7.19-7.10 (2H, m) 7.03-7.00 (1H, t), 6.34 (2H, s),4.22 (1H, s), 3.79 (3H, s)

MASS (m/z): 413

EXAMPLE 53 1-(2-Napthyl-2-oxo-ethyl)-3[(3-methyl)pyrazol-5-yl]pyridiniumbromide

(Compound 52)

Yield: 38%

IR (KBr, cm⁻¹): 3066, 1675, 1518

¹HNMR (DMSO-d6, 400 MHz) δ: 13.25 (1H, s), 9.53 (1H, s) 9.02-9.0 (1H,d), 8.92-8.91 (1H, d), 8.84 (1H, s), 8.32-8.04 (5H, m), 7.79-7.70 (2H,m), 6.75 (1H, s), 6.63 (2H, s), 2.33 (3H, s)

MASS (m/z): 328, 329, 330

EXAMPLE 54 1-(2-(1,4 benzodioxane-6-yl-amino-2-oxoethyl)-3 L(3-phenylmethyl)pyrazol-5-yl]pyridinium chloride

(Compound 53)

Yield: 32%

IR (KBr, cm⁻¹): 3445, 3068, 1678

¹HNMR (DMSO-d6, 400 MHz) δ: 13.45 (1H, s), 10.61 (1H, s), 9.47 (1H, s),8.97-8.95 (1H, d), 8.91-8.89 (1H, d), 8.2 (1H, t), 7.34-7.19 (6H, m),6.99-6.97 (1H, d), 6.84-6.82 (1H, d), 6.72 (1H, s), 5.61 (2H, s), 4.21(4H, s), 4.06 (2H, s)

MASS (m/z): 427, 428, 429

EXAMPLE 551-(2-Thien-2-yl-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]-5-bromopyridiniumchloride

(Compound 54)

Yield: 31%

IR (KBr, cm⁻¹)

¹HNMR (DMSO-d6, 400 MHz) δ: 9.63 (1H, s), 9.36 (1H, s), 9.33 (1H, s),8.27-8.24 (2H, m), 7.81-7.79 (2H, d), 7.57-7.52 (3H, m), 7.46-7.42 (2H,m), 6.40 (2H, s)

MASS (m/z): 426, 427, 428

EXAMPLE 561-(2-Thien-2-yl)-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]quinoliniumchloride

(Compound 55)

Yield: 26%

IR (KBr, cm⁻¹)

¹HNMR (DMSO-d6, 400 MHz) δ: 10.18 (1H, s), 9.81 (1H, s) 8.45-8.40 (3H,m), 8.29-8.28 (1H, d), 8.21 (1H, t), 8.08 (1H, t) 7.87-7.85 (2H, d),7.57-7.55 (3H, m), 7.50-7.45 (2H, m), 6.96 (2H, s)

MASS (m/z): 396, 397, 398

EXAMPLE 57 3-[(3-phenyl)pyrazol-5-yl)]quinoline

(Compound 56)

Yield: 70%

¹HNMR (DMSO-d6, 400 MHz) δ: 9.45 (1H, bs), 8.75 (1H, s), 8.05 (2H, d),7.87 (2H, bs), 7.77 (1H, t), 7.65 (1H, t), 7.55-7.45 (3H, m), 7.39 (1H,bs)

MASS (m/z): 272 (M⁺+1)

Cosmetic Preparation

The preparation for use in cosmetic application may contain one or moreconcentration of the compound in a cosmetically acceptable vehicle. Theamount of the compound of invention will preferably range between 0.005to 50% by weight (unless otherwise noted, all fraction amounts areexpressed in weight percent), more preferably between 0.20% and 5.0%w/w. The composition should be applied based on the requirement to anaffected area.

Suitable vehicles or carriers for storage and/or delivery of the novelcompound of this invention may be provided in lotion, liquid, ointment,gels, creams, spray, poultice or other forms, and will preferably have alipophilic, hydrophilic or amphiphilic character. Suitable carriersinclude petrolatum, triglycerides, various esters, fatty alcohols, fattyacid, alkylene glycols, and ethanol, of which polyethylene glycol andpolypropylene glycol are most preferred; if desired, compatiblecombinations of these vehicles are also suitable.

Further more the vehicles are present as needed for the desired deliverysystem. The vehicles or carriers can also have additional agentsaccording to conventional practice. For example, the final compositionmay contain various emollients, emulsifiers, alcohols, colorants,fragrances, thickeners (such as xanthan gum), preservatives, humectants,surfactants (anionic, cationic, nonionic, amphoteric alone or incombinations), agents which modify skin differentiation and/orproliferation and/or pigmentation, antiparasitic agents, dispersants,opacifier, gelling agent, hydrating agent, additional antioxidants, thetypical botanical extracts such as those derived from aloe, citrusfruits, Witch Hazel, chamomile, and other like e.g., those having anastringent, antiseptic, sunscreens or suntan effects, skin toners,silicones, exfoliating agents, keratolytic agents, retinoids, skinpenetration enhancers, vitamins, thrombolytic agents, anticlottingagents, capillary protectants, hormones, antibacterial agents, antiviralagents, steroidal anti-inflammatory agents, anaesthetics,anti-seborrhoeic agents, anti-dandruff agents, anti-acne agents,anti-free radical agents, analgesics, lipophilic compounds,antihistamine agents, insect repellants, skin cooling compounds,lubricants, anti-fungal agents or mixtures thereof. The composition maylikewise include a penetration enhancer such as, but not limited to,Oleic acid, DMSO (dimethyl sulfoxide), alcohols, N-methylpyrolidone,dimethyl isosorbide. It may also include one or more additional activeingredients such as anti-inflammatory agents, antibiotic, astringents,growth factors, tocopherols, retinols, free radical scavengers.

The following non-limiting examples are for cosmetic compositionaccording to the instant invention.

EXAMPLE 58

Compound of invention  0.3% w/w Oleic acid  10.0% w/w Propylene Glycol 70.0% w/w Tween 80  0.1% w/w Absolute ethanol.qs 100.0% w/w

EXAMPLE 59

Compound of invention  0.3% w/w Oleic acid  10.0% w/w ColliodalsiliconDioxide  6.0% w/w Tween 80  0.1% w/w Caprylic capricTriglyceride qs100.0% w/w

A cosmetically acceptable organic fatty acid can optionally be presentindependently in the composition in an amount, preferably a bioactivelyeffective amount, of 0.1% to 10.0%; the addition of fatty acid is apreferred ingredient.

The effect of the compound of invention synergistically improves whencombined with a humectant, an emollient, additional antioxidants or ananti-inflammatory agent.

EXAMPLE 60

Compound of invention 0.4% w/w Fatty acid 4.0% w/w Mineral oil 5.0% w/wIsocetyl stearate 1.0% w/w Antioxidant 0.05% w/w Xanthan gum 0.2% w/wGlycerol 50.0% w/w Diazolidinyl urea 0.2% w/w Lemon peel Extract 0.02%w/w Alcohol 2.0% w/w Purified water 100.0% w/w

The addition of humectants and emollients to the antioxidant compositionis expected to aid in the rehydration and maintenance of hydration ofthe skin under consideration. Improved hydration of the skin is believedto both increase the absorbence of the free radical scavenger by theskin and helps in the delivery of the free radical scavenger to theactive site.

Examples of the emollients which can be used are: mineral oil,petrolatum, paraffin, ceresin, ozokerite, microcrystalline wax,perhydrosqualene dimethyl polysiloxanes, methylphenyl polysiloxanes,silicone, silicone-glycol copolymers, triglyceride esters, acetylatedmonoglycerides, ethoxylated glycerides, alkyl esters of fatty acids,fatty acids and alcohols, lanolin and lanolin derivatives, polyhydricalcohol esters, sterols, beeswax derivatives, polyhydric alcohols andpolyethers, and amides of fatty acids. Although various emollients knownin the art would be useful in the present invention, the preferredemollient is silicone.

Humectants known in the art to increase skin hydration when appliedtopically, such as polyhydric alcohols, are appropriate. Examples ofsuitable humectants are: glycerin, propylene glycol, butylene glycol,diglycerol, or ester derivatives thereof. However, the preferredhumectant is glycerin.

The topical preparation of the present invention may contain a singleantioxidant, apart from the compound of the invention or a combinationof antioxidants, thus an antioxidant blend. The term “antioxidant” asused herein is intended to encompass both a single antioxidant as wellas an antioxidant blend. The antioxidant may also be incorporated intovarious vehicles to facilitate topical application.

In order to obtain elegant, topical compositions in the form of cream,emulsions, lotions or gels, such compositions may include from about0.001 wt % to about 50 wt % of an antioxidant.

The topical compositions of the present invention can be made as lotionsand creams.

The free radical scavenger can be combined with most emulsifiers thatare used to make lotions, creams and other suitable topical vehicles.The emulsifiers can be cationic, anionic, nonionic, amphoteric, or acombination thereof. Nonionic emulsifiers are preferred. Exemplarynonionic emulsifiers are commercially available sorbitans, alkoxylatedfatty alcohols and alkyl polyglycosides. Anionic emulsifiers may includesoaps, alkyl sulfates, monoalkyl and dialkyl phosphates, alkylsulphonates and acyl isothionates, an amphoteric emulsifier that may beused is lactamidopropyl trimonium chloride.

Suitable vehicles for composition of the present invention may alsocontain thickeners. Examples of suitable thickeners include cellulosederivatives, such as hydroxyethyl cellulose and hydroxypropyl cellulose,as well as polyacrylic acid polymers.

Examples of preservatives that are suitable for use with thecompositions include alkanols, especially ethanol and benzyl alcohol;parabens; sorbates; urea derivatives; and, isothiazolinones.

Lotions or creams according to the present invention can be made usingconventional homogenization methods known to those skilled in the art.It is also possible to use a process of microfluidization that involvesco-mixing the aqueous phase and the oil phase of such creams and lotionsin a high-pressure homogenizer that reduces the emulsion particle sizedramatically to about several microns of those in creams and lotionsprepared without applying high pressure. Microfluidization allows one toprepare elegant stable creams and lotions containing effective amountsof the compound without the use of traditional emulsifiers andsurfactants.

The topical compositions of the present invention can also be formulatedas a micro-emulsion, which is a subcategory of emulsions, oils that maybe used are mineral oil and silicone oil. Examples of alcohols that maybe used are cetyl alcohol, isostearyl alcohol, stearyl alcohol,dodecanol and dodecenol. Nonionic surfactants may be fatty esters,esters of fatty alcohols or ethoxylated alcohols. Examples of nonionicsurfactants are polyethylene glycol, isopropyl myristate, cetylisooctadecanoate, polypropylene glycols, sorbitants and isopropyloleate.

EXAMPLE 61

Compound of invention  0.2% w/w Fatty acid  1.5% w/w Surfactant  3.0%w/w Cosolvent  70.0% w/w Purified water . . . (qs) 100.0% w/w

The topical compositions of the invention can be formulated asoil-in-water or water-in-oil emulsions. The compositions can also be inthe form of a multiphase emulsion, such as a water-in-oil-in-water typeemulsion

The compositions of the invention can also be made as a liposomalformulation. In such compositions, compound solution can be entrappedinside the liposomal vesicles with the shell of the liposome being aphospholipid or other suitable lipids (e.g. skin lipids). To form atopical composition, the liposomes can then be added to any carriersystem described above according, to the preparation modes, uses andcompositions of topical liposomes.

EXAMPLE 62

Compound of invention  0.4% w/w Phospholipid  6.0% w/w Antioxidants  05% w/w Ethanol  15.0% w/w Hydrophilic medium . . . (qs) 100.0% w/w

Solutions of compound and antioxidants can also be entrapped inpolymeric vesicles with a shell comprising of a suitable polymericmaterial, such as gelatin, cross-linked gelatin, polyamide,polyacrylates and the like to form a vesicle that is then incorporatedinto the topical composition.

The composition according to the instant invention can be used for oneor more of the following cosmetic applications, namely (a) reversing andpreventing wrinkles b) reversing and preventing fine lines (c) promotingepidermal growth (d) photo protection (e) reversing and preventing skindiscoloration (f) reversing and preventing age spots (g) conditioningand preventing dryness (h) reversing and preventing stretch marks (i)reversing and preventing blemishes (j) skin care/skin conditioning (k)reversing and preventing senile xerosis (l) conditioning and preventingsun burns (m) preventing and reversing the loss of collagen (n)improving skin texture (O) improving skin tone (p) enhancing skinthickness (q) decreasing pore size (r) restoring skin luster (s)minimizing signs of fatigue (t) reducing acne, (u) treatment ofTelangiectasia and (v) improving asthetic appearance of hair and nail.

Pharmaceutical Compositions

Pharmaceutical compositions effective for scavenging free radicalsand/or inhibiting AGE may be prepared with a pharmaceutically effectivequantity of compounds of general formula 1, individually or incombination. The amount of the compound of invention will preferablyrange between 0.00001 to 90% by weight. The following pharmaceuticalformulations suggested are by way of example alone and in no wayrestrict the scope of the invention.

Oral Formulations

Oral formulations may be administered as solid dosage forms for examplepellets, powders, sachets or discreet units such as tablets or capsulesand like. Other orally administered pharmaceutical preparations includemonophasic and biphasic liquid dosage forms either in ready to use formor forms suitable for reconstitution such as mixtures, syrups,suspensions or emulsions. The preparations in addition may containdiluents, dispersing agents, buffers, stabilizers, solubilizers,surfactants, preservatives, chelating agents and/or other pharmaceuticaladditives as are used. Aqueous or non aqueous vehicle or theircombination may be used and if desired may contain suitable sweetener,flavoring agent or similar substances. In case of suspension or emulsiona suitable thickening agent or suspending agent or emulsifying agent maybe present in addition. Alternatively, the compounds may be administeredas such in their pure form unassociated with other additives for exampleas capsules or sachets. It may also be administered with a vehicle.Pharmaceutical preparations can have a slow, delayed or controlledrelease of active ingredients as is provided by a matrix or diffusioncontrolled system.

When the present invention or its salts or suitable complexes ispresented as a discreet unit dosage form like tablet, it may contain inaddition medically inert excipients as are used in the art. Diluentssuch as starch, lactose, dicalcium phosphate, talc, magnesium stearate,polymeric substances like methyl cellulose, fatty acids and derivatives,sodium starch glycollate, etc. may also be used.

EXAMPLE 63

Preparation of Oral Dosage Form: A typical tablet can have the followingcomposition: Active ingredient of general formula I an effective amountLactose 100 mg Microcrystaline Cellulose  51 mg Starch  60 mg Polyvinylpyrolidone (K-30)  2 mg Talc  1.5 mg Magnesium Stearate  1.0 mg ORActive ingredient of general formula I an effective amount Lactose 130mg Starch  75 mg Polyvinyl pyrolidone (K-30)  2 mg Talc  1.5 mgMagnesium Stearate  1.0 mgParenteral Formulations

For parenteral administration, the compounds or their salts or suitablecomplexes thereof may be present in a sterile vehicle which may be anaqueous or non aqueous vehicle or a combination thereof. The examples ofvehicles are water, ethyl oleate, oils and derivatives of polyols,glycols and their derivatives. It may contain additives common ininjectable preparations like stabilizers, solubilizers, pH modifiers,buffers, antioxidants, cosolvents, complexing agents, tonicitymodifiers, etc.

Some suitable additives are for example tartrate, citrate or similarbuffers, alcohol, sodium chloride, dextrose and high molecular weightpolymers. Another alternative is sterile powder reconstitution. Thecompound may be administered in the form of injection for more than oncedaily administration, or intravenous infusion/drip or suitable depotpreparation.

EXAMPLE 64

Preparation for Parenteral Administration Active ingredient of generalformula I an effective amount Polethylene glycol (400)   20% w/v Sodiummetabisulphite 0.01% w/v Isotonic saline/WFI q.s. to 100%Other Formulations.

For the dermatological application and for the discoloration of teeth;the recommended formulations are lotions, oral rinse and toothpastecontaining appropriate amount of the compounds of the general formula I.

The above examples are presented by way of illustration alone and in noway limit the scope of the invention.

1. A compound represented by formula (I) and its pharmaceutically orcosmetically acceptable salts

wherein, R₁ is hydrogen or selected from linear or branched (C₁-C₁₂)alkyl, (C₂-C₁₂) alkenyl, (C₃-C₇) cycloalkyl, (C₅-C₇) cycloalkenyl,bicycloalkyl, bicycloalkenyl, heterocycloalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl and wherein one or more heteroatoms whenpresent are independently selected from O, N, or S and is optionallysubstituted, wherein the substituents are selected from a first groupconsisting of halogen, hydroxy, nitro, cyano, amino, oxo and oxime orfrom a second group consisting of linear or branched (C₁-C₈) alkyl,(C₃-C₇) cycloalkyl, alkylcycloalkyl, perhaloalkyl, perhalocycloalkyl,aryl, aralkyl, alkylaryl, alkylheteroaryl, aralkoxylalkyl, perhaloaryl,alkylheterocycloalkyl, heterocyclyloalkyl, perhaloheterocyclyloalkyl,heteroaryl, heteroaralkyl, alkylaryl, perhaloheteroaryl, acyl,alkoxyalkyl, thioalkyl and thioaryl, wherein the substitutents from saidsecond group are optionally substituted by R₁₀ and are optionally andindependently bridged by —(CO)O—, —(CO)NH—, —NH—, —NR₈—, —O—, —S—,—(SO)—, —(SO₂), —(SO₂)NH—, or —NH(CO)—; Y is selected from the groupconsisting of null, (C₁-C₁₂) alkyl-Z or (C₂-C₁₂) alkyl, wherein Z isselected from sulfur, oxygen or nitrogen; A and B are independentlyselected from NH, NR6, sulfur, oxygen or carbon to form a heteroaromaticring system; R₂, R₃ and R₄ are independently selected from a first groupconsisting of hydrogen, halogen, NO₂, N═C(R₈)(R₉), —NR₈R₉, —OR₈,perhaloalkyl, —(CO)NR₈R₉, —(CO)R₈, —(CO)OR₈, —O(CO)R₈, —NH(CO)R₈ or froma second group consisting of linear or branched (C1-C12)alkyl,(C2-C12)alkenyl, (C3-C7)cycloalkyl, (C5-C7)cycloalkenyl, bicycloalkyl,bicycloalkenyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, wherein one or more members of said second group whenpresent are optionally substituted by R10 and wherein one or moreheteroatoms when present are independently selected from O, N, or S; R₅is null or selected from the group consisting of linear or branched(C₁-C₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₃-C₇)cycloalkyl, (C₅-C₇)cycloalkenyl,bicycloalkyl; CH₂(CO)R₇, CH₂(CO)NHR₈, CH₂(CO)NR₈R₉, and CH₂(CO)OR₇ whichare optionally substituted by R₁₀; R₆ and R₇ are independently selectedfrom the group consisting of linear or branched (C₁-C₈) alkyl,(C₃-C₇)cycloalkyl, alkylcycloalkyl, perhaloalkyl, perhalocycloalkyl,aryl, aralkyl, alkylaryl, alkylheteroaryl, aralkoxylalkyl, perhaloaryl,alkylheterocycloalkyl, heterocyclyloalkyl, perhaloheterocyclyloalkyl,heteroaryl, heteroaralkyl, alkylaryl, perhaloheteroaryl, acyl, benzoyl,alkoxyalkyl, thioalkyl and thioaryl wherein members of said group areoptionally substituted by R₁₀; R₈ and R₉ are independently selected fromthe group consisting of linear or branched (C₁-C₁₂)alkyl, alkoxyaryl,alkoxyalkyl, alkoxycycloalkyl, alkoxyaryl, perhaloalkyl,(C₂-C₁₂)alkenyl, (C₃-C₇)cycloalkyl, perhalocycloalkyl,haloheterocycloalkyl, cyanoheterocycloalkyl, perhaloheterocycloalkyl,(C₅-C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, heterocycloalkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, perhaloaryl, perhaloheteroarylwherein substituents of said group are optionally substituted by R₁₀;R₁₀ is selected from halogen, hydroxy, nitro, cyano, amino, oxo,perhaloalkyl(C₁-C₆), or oxime; X is selected from group comprising of ahalide ion, acetate ion, perchlorate ion, sulfonate ion, oxalate ion,citrate ion, tosylate ion, maleate ion, mesylate ion, carbonate ion,sulfite ion, phosphoric hydrogen ion, phosphonate ion, phosphate ion,BF₄ ⁻ and PF₆ ⁻ provided when the groups/substituents are present onsame or adjacent carbon or nitrogen atoms they together may optionallyform a five or a six or a seven membered ring optionally containing oneor more double bonds and optionally containing one or more heteroatomsselected from O, N, or S.
 2. The compound as claimed in claim 1, whereinsaid pharmaceutically/cosmetically acceptable salts are salts of thecarboxylic acid selected from alkali metal salts and alkaline earthmetal salts; salts of organic bases selected from lysine, arginine,guanidine, diethanolamine and choline; ammonium or substituted ammoniumsalts, aluminium salts; or acid addition salts selected form the groupconsisting of sulfates, nitrates, phosphates, perchlorates, borates,hydrohalides, acetates, tartrates, maleates, citrates, succinates,palmoates, methanesulfonates, benzoates, salicylates,hydroxynaphthoates, benzensulfonates, ascorbates, glycerophosphates andketoglutarates.
 3. A compound as claimed in claim 1, wherein R₁ is asubstituted or unsubstituted group selected from linear or branched(C₁-C₁₂)alkyl, (C₃-C₇)cycloalkyl, heterocycloalkyl, aryl or heteroaryl;wherein one or more heteroatoms when present are independently selectedfrom O, N, or S.
 4. A compound as claimed in claim 1, wherein Y isselected from the group consisting of null (C₁-C₈) alkyl-Z and (C₁-C₈)alkyl, wherein Z is selected from sulfur, oxygen or nitrogen.
 5. Acompound as claimed in claim 1, wherein A and B are independentlyselected from NH and NR₆.
 6. A compound as claimed in claim 1, whereinR₂, R₃ and R₄ are independently selected from the group consisting ofhydrogen, halogen, NO₂ and perhaloalkyl.
 7. A compound as claimed inclaim 1, wherein R₅ is either null or selected from the group CH₂(CO)R₇and CH₂(CO)NHR₈, optionally substituted by R₁₀.
 8. A compound as claimedin claim 1, wherein X is halide.
 9. A compound as claimed in claim 1,which is selected from the group consisting of the following compound orpharmaceutically acceptable salts thereof: a)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide; b) 1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)oxazol-5-ylpyridinium bromide; c)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(2-thien-2′-yl)-2-oxoethylpyridinium-4-thio}methyl-pyrazol-5-yl]pyridinium dibromide; d)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(3,5-dimethylpyrazol-1-yl)methyl}pyrazol-5-yl]pyridiniumbromide; e)1-(2-thien-2′-yl-2-oxoethyl)-3-[{3-phenylmethyl}-1-{2-pyridyl}-pyrazol-5-yl]-pyridiniumbromide; f) 1-(2-thien-2′-yl-2-oxoethyl)-3-[3{(3,5-dimethylpyrazol-1-yl)methyl-1-pyridyl}pyrazol-5-yl]pyridiniumbromide; g)1-[2-(cyclopropylamino)-2-oxoethyl]3-[3-{(3,5-dimethylpyrazol-1-yl)methyl}-pyrazol-5-yl]-pyridiniumbromide; h) 1-{2-(4-nitro-2-thienyl)-2-oxoethyl}-3-[3{(3,5-dimethylpyrazol-1-yl)ethyl}-pyrazol-5-yl]-pyridinium bromide; i)1-(2-cyclopropylamino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride; j)3,5-bis-[1-(2-thien-2′-yl-2-oxoethyl)-pyridinium-3-yl]-pyrazoledibromide; k)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride; l)1-(2-(5′-methyl-2-thienyl)-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride; m)1-(2-thien-2′-yl-2-oxoethyl)3-[1-phenyl,3-{(3,5-dimethylpyrazol-1-yl)methyl)}pyrazol-5-yl]-pyridiniumchloride; n)1-(2-phenyl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]-pyridiniumbromide; o)1-(2-cyclopropylamino-2-oxoethyl)3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride; p)1-(2-(4-benzyl-1-piperidinyl)-2-oxoethyl)3-[(3-phenoxymethyl)pyrazol-5-yl]-pyridiniumbromide; q)1-(2-phenyl-2-oxoethyl)-3-[(3-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]-pyridiniumchloride; r)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3,-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]pyridiniumchloride; s)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride; t)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride; u)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride; v)1-(2-phenyl-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride; w)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride; x)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride; y)1-[2-(1-adamantylamino)-2-oxoethyl]-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride; z)1-(2-phenyl-2-oxoethyl)-3-[{3-(3,5-dimethylpyrazol-1-yl)methyl)}1-phenyl-pyrazol-5-yl]pyridiniumbromide; aa)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl)-methyl)pyrazol-5-yl]pyridiniumbromide; bb)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide; cc)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride; dd)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide; ee)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride; ff)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl)methyl)pyrazole-5-yl]pyridiniumchloride; gg)1-(2-(5-chloro-2-thienyl)-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide; hh)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride; ii)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridiniumchloride; jj)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide; kk)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide; ll)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride; mm) 3-[(3-phenylmethyl)pyrazol-5-yl]pyridine hydrochloride;nn) 3-[(3-phenoxymethyl)pyrazol-5-yl]pyridine hydrochloride; oo)3-[(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridine; pp)3-[3-(2-cyclohexyl-ethyl)-pyrazol-5-yl]pyridine; qq)1-(2-napthyl-2-oxoethyl)-3[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide; rr) 1-(phenylmethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride; ss)1-(2-thien-2′-yl-2-oxoethyl)-3[(3(-1-naphthyl)pyrazol-5-yl]pyridiniumchloride; tt)1-(2-phenyl-2oxoethyl)-3[3(thienyl-2-yl-methyl)pyrazol-5-yl]pyridiniumchloride; uu)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[3(2-phenylethyl)pyrazol-5-yl]pyridiniumchloride; vv) 1-(2-(5-methyl2-thienyl)-2-oxoethyl)-3-[3-(3-phenoxypropyl)pyrazol-5-yl]pyridiniumchloride; ww) 1-(isopropyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide; xx)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3-thiophenylmethyl)pyrazol-5-yl]pyridiniumchloride; yy) 1-(2-thien-2′-yl-2-oxoethyl)-3[(3-(N-methyl-indole-3-ylmethyl)pyrazol-5-yl]pyridinium chloride; zz)1-(2-napthyl-2-oxo-ethyl)-3[(3-methyl)pyrazol-5-yl]pyridinium bromide;aaa) 1-(2-(1,4benzodioxane-6-yl-amino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride; bbb) 1-(2-thien-2′-yl)-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]-5bromo pyridinium chloride; ccc)1-(2-thien-2′-yl)-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]quinoliniumchloride and ddd) 3-[(3-phenyl)pyrazol-5-yl)]quinoline.
 10. A processfor the preparation of the compound of general formula (I) as defined inclaim 1, which comprises the steps of: (a) preparing the corresponding1,3 diketo compound by reacting unsubstituted/substituted acetylpyridines with alkyl/aryl esters in a suitable base or by reactingunsubstituted/substituted aryl esters with unsubstituted/substitutedaryl methyl ketone in a suitable base; (b) cyclizing of the productobtained in step (a) and optionally; (c) quaternizing the substitutedpyridine obtained in step (b), with a quaternizing agent in an alcoholicand/or high boiling solvent under reflux for 6-48 hrs. to give thedesired compound.
 11. A pharmaceutical composition comprising apharmaceutically effective amount of one or more compounds of generalformula (I), as defined in claim 1 or pharmaceutically acceptablesalt(s) thereof in admixture with a pharmaceutically acceptable carrier,diluent, solvent or excipient.
 12. A pharmaceutical composition asclaimed in claim 11, in the form of an oral formulation.
 13. Apharmaceutical composition as claimed in claim 11, wherein saidacceptable carrier, diluent, solvent or excipient is selected from groupcomprising of starch, lactose, polyvinyl pyrolidone (K-30), talc andmagnesium stearate.
 14. A pharmaceutical composition as claimed in claim11 in the form of a parenteral formulation.
 15. A method for thepreparation of a parenteral formulation as claimed in claim 14, whichcomprises dissolving one or more compounds of general formula (I), asdefined in claim 1, in polyethylene glycol 400 and diluting the solutionso obtained, with an isotonic solution or water to a desiredconcentration.
 16. A pharmaceutical composition as claimed in claim 11,in the form of a lotion, oral rinse and toothpaste.
 17. A pharmaceuticalcomposition as claimed claim 11 wherein said compound is selected fromthe group consisting of: a)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; b)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)oxazol-5-yl pyridiniumbromide or a pharmaceutically acceptable salt thereof; c)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(2-thien-2′-yl)-2-oxoethylpyridinium-4-thio}methyl-pyrazol-5-yl]pyridinium bromide or apharmaceutically acceptable salt thereof; d)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(3,5-dimethylpyrazol-1-yl)methyl}pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; e)1-(2-thien-2′-yl-2-oxoethyl)-3-[{3-phenylmethyl}-1-{2-pyridyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; f)1-(2-thien-2′-yl-2-oxoethyl)-3-[3{(3,5-dimethylpyrazol-1-yl)methyl-1-pyridyl}pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; g)1-[2-(cyclopropylamino)-2-oxoethyl]3-[3-{(3,5-dimethylpyrazol-1-yl)methyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; h)1-{2-(4-nitro-2-thienyl)-2-oxoethyl}-3-[3{(3,5-dimethylpyrazol-1-yl)ethyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; i)1-(2-cyclopropylamino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; j)3,5-bis-[1-(2-thien-2′-yl-2-oxoethyl)-pyridinium-3-yl]-pyrazoledibromide and pharmaceutically acceptable salts thereof or apharmaceutically acceptable salt thereof; k)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; l)1-(2-(5′-methyl-2-thienyl)-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; m)1-(2-thien-2′-yl-2-oxoethyl)3-[1-phenyl,3-{(3,5-dimethylpyrazol-1-yl)methyl)}pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; n)1-(2-phenyl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; o)1-(2-cyclopropylamino-2-oxoethyl)3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; p)1-(2-(4-benzyl-1-piperidinyl)-2-oxoethyl)3-[(3-phenoxymethyl)pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; q)1-(2-phenyl-2-oxoethyl)-3-[(3-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; r)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3,-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; s)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; t)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; u)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; v)1-(2-phenyl-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; w)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; x)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; y)1-[2-(1-adamantylamino)-2-oxoethyl]-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; z)1-(2-phenyl-2-oxoethyl)-3-[{3-(3,5-dimethylpyrazol-1-yl)methyl)}1-phenyl-pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; aa)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl)-methyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; bb)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; cc)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; dd)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; ee)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ff)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrozol-1-yl)methyl)pyrazole-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; gg)1-(2-(5-chloro-2-thienyl)-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; hh)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ii)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; jj)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; kk)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; ll)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; mm)3-[(3-phenylmethyl)pyrazol-5-yl]pyridine hydrochloride or apharmaceutically acceptable salt thereof; nn)3-[(3-phenoxymethyl)pyrazol-5-yl]pyridine hydrochloride or apharmaceutically acceptable salt thereof; oo)3-[(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridine or apharmaceutically acceptable salt thereof; pp)3-[3-(2-cyclohexyl-ethyl)-pyrazol-5-yl]pyridine or a pharmaceuticallyacceptable salt thereof; qq)1-(2-napthyl-2-oxoethyl)-3[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; rr)1-(phenylmethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium chloride or apharmaceutically acceptable salt thereof; ss)1-(2-thien-2′-yl-2-oxoethyl)-3[(3(-1-naphthyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; tt)1-(2-phenyl-2oxoethyl)-3[3(thienyl-2-yl-methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; uu)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[3(2-phenylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; vv)1-(2-(5-methyl2-thienyl)-2-oxoethyl)-3-[3-(3-phenoxypropyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ww)1-(isopropyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium bromide or apharmaceutically acceptable salt thereof; xx)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3-thiophenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; yy)1-(2-thien-2′-yl-2-oxoethyl)-3[(3-(N-methyl-indole-3-ylmethyl)pyrazol-5-yl]pyridinium chloride or a pharmaceutically acceptablesalt thereof; zz)1-(2-napthyl-2-oxo-ethyl)-3[(3-methyl)pyrazol-5-yl]pyridinium bromide ora pharmaceutically acceptable salt thereof; aaa) 1-(2-(1,4benzodioxane-6-yl-amino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; bbb)1-(2-thien-2′-yl-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]-5bromo-pyridinium chloride or a pharmaceutically acceptable salt thereof;ccc) 1-(2-thien-2-′yl)-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]quinoliniumchloride or a pharmaceutically acceptable salt thereof and ddd)3-[(3-phenyl)pyrazol-5-yl)]quinoline or a pharmaceutically acceptablesalt thereof.
 18. A method for treating a mammal for diseases, caused bythe accumulation of AGE, by breaking a preformed AGE, within saidmammal, which comprises, administering an effective amount of a compoundof formula (I) as defined in claim 1, either singly, or in combinationwith other drugs for antidiabetic therapy with a pharmaceuticallyacceptable carrier, diluent or excipient.
 19. The method as claimed inclaim 18 wherein the disease caused to be treated is selected fromdiabetes and aging related vascular or neurovascular disorders.
 20. Themethod as claimed in claim 18 wherein the disease caused to be treatedthereby is selected from diabetes and aging related vascular orneurovascular disorders.
 21. The method as claimed in claim 18, whereinthe disease caused to be treated, is selected from the group consistingof nephrological disorder, neurological disorder, atherosclerosis,retinal disorder, inflammatory disorder, immunological disorder,oxidative stress, non-enzymatic browning of oral cavity, endothelial orother organ dysfunction and growth impairment.
 22. The method as claimedin claim 18, wherein the disease caused to be treated is selected fromthe group consisting of alzheimer disease, restenosis, abnormal tissuehindrance in peritoneal dialysis and erectile dysfunction.
 23. Themethod as claimed in claim 18, wherein said compound is selected fromthe group comprising of: a)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; b)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)oxazol-5-yl pyridiniumbromide or a pharmaceutically acceptable salt thereof; c)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(2-thien-2′-yl)-2-oxoethylpyridinium-4-thio}methyl-pyrazol-5-yl]pyridinium bromide or apharmaceutically acceptable salt thereof; d)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(3,5-dimethylpyrazol-1-yl)methyl}pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; e)1-(2-thien-2′-yl-2-oxoethyl)-3-[{3-phenylmethyl}-1-{2-pyridyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; f)1-(2-thien-2′-yl-2-oxoethyl)-3-[3{(3,5-dimethylpyrazol-1-yl)methyl-1-pyridyl}pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; g)1-[2-(cyclopropylamino)-2-oxoethyl]3-[3-{(3,5-dimethylpyrazol-1-yl)methyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; h)1-{2-(4-nitro-2-thienyl)-2-oxoethyl}-3-[3{(3,5-dimethylpyrazol-1-yl)ethyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; i)1-(2-cyclopropylamino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; j)3,5-bis-[1-(2-thien-2′-yl-2-oxoethyl)-pyridinium-3-yl]-pyrazoledibromide and pharmaceutically acceptable salts thereof or apharmaceutically acceptable salt thereof; k)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; l)1-(2-(5′-methyl-2-thienyl)-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; m)1-(2-thien-2′-yl-2-oxoethyl)3-[1-phenyl,3-{(3,5-dimethylpyrazol-1-yl)methyl)}pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; n)1-(2-phenyl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; o)1-(2-cyclopropylamino-2-oxoethyl)3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; p)1-(2-(4-benzyl-1-piperidinyl)-2-oxoethyl)3-[(3-phenoxymethyl)pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; q)1-(2-phenyl-2-oxoethyl)-3-[(3-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; r)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3,-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; s)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; t)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; u)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; v)1-(2-phenyl-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; w)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; x)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; y)1-[2-(1-adamantylamino)-2-oxoethyl]-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; z)1-(2-phenyl-2-oxoethyl)-3-[{3-(3,5-dimethylpyrazol-1-yl)methyl)}1-phenyl-pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; aa)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl)-methyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; bb)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; cc)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; dd)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; ee)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ff)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrozol-1-yl)methyl)pyrazole-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; gg)1-(2-(5-chloro-2-thienyl)-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; hh)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ii)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; jj)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; kk)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; ll)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; mm)3-[(3-phenylmethyl)pyrazol-5-yl]pyridine hydrochloride or apharmaceutically acceptable salt thereof; nn)3-[(3-phenoxymethyl)pyrazol-5-yl]pyridine hydrochloride or apharmaceutically acceptable salt thereof; oo)3-[(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridine or apharmaceutically acceptable salt thereof; pp)3-[3-(2-cyclohexyl-ethyl)-pyrazol-5-yl]pyridine or a pharmaceuticallyacceptable salt thereof; qq)1-(2-napthyl-2-oxoethyl)-3[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; rr)1-(phenylmethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium chloride or apharmaceutically acceptable salt thereof; ss)1-(2-thien-2′-yl-2-oxoethyl)-3[(3(-1-naphthyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; tt)1-(2-phenyl-2oxoethyl)-3[3(thienyl-2-yl-methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; uu)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[3(2-phenylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; vv)1-(2-(5-methyl2-thienyl)-2-oxoethyl)-3-[3-(3-phenoxypropyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ww)1-(isopropyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium bromide or apharmaceutically acceptable salt thereof; xx)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3-thiophenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; yy)1-(2-thien-2′-yl-2-oxoethyl)-3[(3-(N-methyl-indole-3-ylmethyl)pyrazol-5-yl]pyridinium chloride or a pharmaceutically acceptablesalt thereof; zz)1-(2-napthyl-2-oxo-ethyl)-3[(3-methyl)pyrazol-5-yl]pyridinium bromide ora pharmaceutically acceptable salt thereof; aaa) 1-(2-(1,4benzodioxane-6-yl-amino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; bbb)1-(2-thien-2′-yl-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]-5bromo-pyridinium chloride or a pharmaceutically acceptable salt thereof;ccc) 1-(2-thien-2-′yl)-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]quinoliniumchloride or a pharmaceutically acceptable salt thereof and ddd)3-[(3-phenyl)pyrazol-5-yl)]quinoline or a pharmaceutically acceptablesalt thereof.
 24. A method for treating a mammal, to inhibitaccumulation of AGE, by breaking AGE, which comprises, administering toa mammal in need thereof, an effective amount of a compound generalformula (I), as defined in claim 1, either singly or in combination withother drugs for antidiabetic thereby in a pharmaceutically acceptablecarrier, diluent or excipient.
 25. The method as claimed in claim 24wherein disease caused to be treated thereby is selected from anephrological disorder, neurological disorder, atherosclerosis, retinaldisorder, inflammatory disorder, immunological disorder, oxidativestress, non-enzymatic browning of oral cavity, endothelial or otherorgan dysfunction and growth impairment.
 26. The method as claimed inclaim 24 wherein the disease caused to be treated thereby is selectedfrom alzheimer disease, restenosis, abnormal tissue hindrance inperitoneal dialysis and erectile dysfunction.
 27. The method as claimedin claim 24, wherein said compound is selected from the group consistingof: a)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; b)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)oxazol-5-yl pyridiniumbromide or a pharmaceutically acceptable salt thereof; c)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(2-thien-2′-yl)-2-oxoethylpyridinium-4-thio}methyl-pyrazol-5-yl]pyridinium bromide or apharmaceutically acceptable salt thereof; d)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(3,5-dimethylpyrazol-1-yl)methyl}pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; e)1-(2-thien-2′-yl-2-oxoethyl)-3-[{3-phenylmethyl}-1-{2-pyridyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; f)1-(2-thien-2′-yl-2-oxoethyl)-3-[3{(3,5-dimethylpyrazol-1-yl)methyl-1-pyridyl}pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; g)1-[2-(cyclopropylamino)-2-oxoethyl]3-[3-{(3,5-dimethylpyrazol-1-yl)methyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; h)1-{2-(4-nitro-2-thienyl)-2-oxoethyl}-3-[3{(3,5-dimethylpyrazol-1-yl)ethyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; i)1-(2-cyclopropylamino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; j)3,5-bis-[1-(2-thien-2′-yl-2-oxoethyl)-pyridinium-3-yl]-pyrazoledibromide and pharmaceutically acceptable salts thereof or apharmaceutically acceptable salt thereof; k)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; l)1-(2-(5′-methyl-2-thienyl)-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; m)1-(2-thien-2′-yl-2-oxoethyl)3-[1-phenyl,3-{(3,5-dimethylpyrazol-1-yl)methyl)}pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; n)1-(2-phenyl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; o)1-(2-cyclopropylamino-2-oxoethyl)3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; p)1-(2-(4-benzyl-1-piperidinyl)-2-oxoethyl)3-[(3-phenoxymethyl)pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; q)1-(2-phenyl-2-oxoethyl)-3-[(3-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; r)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3,-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; s)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; t)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; u)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; v)1-(2-phenyl-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; w)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; x)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; y)1-[2-(1-adamantylamino)-2-oxoethyl]-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; z)1-(2-phenyl-2-oxoethyl)-3-[{3-(3,5-dimethylpyrazol-1-yl)methyl)}1-phenyl-pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; aa)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl)-methyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; bb)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; cc)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; dd)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; ee)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ff)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrozol-1-yl)methyl)pyrazole-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; gg)1-(2-(5-chloro-2-thienyl)-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; hh)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ii)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; jj)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; kk)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; ll)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; mm)3-[(3-phenylmethyl)pyrazol-5-yl]pyridine hydrochloride or apharmaceutically acceptable salt thereof nn)3-[(3-phenoxymethyl)pyrazol-5-yl]pyridine hydrochloride or apharmaceutically acceptable salt thereof; oo)3-[(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridine or apharmaceutically acceptable salt thereof; pp)3-[3-(2-cyclohexyl-ethyl)-pyrazol-5-yl]pyridine or a pharmaceuticallyacceptable salt thereof; qq)1-(2-napthyl-2-oxoethyl)-3[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; rr)1-(phenylmethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium chloride or apharmaceutically acceptable salt thereof; ss)1-(2-thien-2′-yl-2-oxoethyl)-3[(3(-1-naphthyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; tt)1-(2-phenyl-2oxoethyl)-3[3(thienyl-2-yl-methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; uu)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[3(2-phenylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; vv)1-(2-(5-methyl2-thienyl)-2-oxoethyl)-3-[3-(3-phenoxypropyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ww)1-(isopropyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium bromide or apharmaceutically acceptable salt thereof; xx)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3-thiophenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; yy)1-(2-thien-2′-yl-2-oxoethyl)-3[(3-(N-methyl-indole-3-ylmethyl)pyrazol-5-yl]pyridinium chloride or a pharmaceutically acceptablesalt thereof; zz)1-(2-napthyl-2-oxo-ethyl)-3[(3-methyl)pyrazol-5-yl]pyridinium bromide ora pharmaceutically acceptable salt thereof; aaa) 1-(2-(1,4benzodioxane-6-yl-amino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; bbb)1-(2-thien-2′-yl-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]-5bromo-pyridinium chloride or a pharmaceutically acceptable salt thereof;ccc) 1-(2-thien-2-′yl)-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]quinoliniumchloride or a pharmaceutically acceptable salt thereof and ddd)3-[(3-phenyl)pyrazol-5-yl)]quinoline or a pharmaceutically acceptablesalt thereof;
 28. A method for treating and/or preventing diseasescaused by accumulation of AGE in a mammal, by inhibiting the formationof AGE, within said mammal, which comprises, administering an effectiveamount of a compound of formula (I) as defined in claim 1, eithersingly, or in combination with other drugs for antidiabetic therapy in apharmaceutically acceptable carrier, diluent or excipient.
 29. Themethod as claimed in claim 28, wherein the disease caused to be treatedand/or prevented thereby is selected from diabetes and aging relatedvascular and neurovascular disorders.
 30. The method as claimed in claim28, wherein the disease caused to be treated and/or prevented thereby isselected from alzheimer disease, restenosis, abnormal tissue hindrancein peritoneal dialysis and erectile dysfunction.
 31. The method asclaimed in claim 28, wherein the disease caused to be treated and/orprevented thereby is selected from nephrological disorder, neurologicaldisorder, atherosclerosis, retinal disorder, inflammatory disorder,immunological disorder, oxidative stress, non-enzymatic browning of oralcavity, endothelial or other organ dysfunction and growth impairment.32. The method as claimed in claim 28 wherein said compound is selectedfrom the group consisting of: a)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; b)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)oxazol-5-yl pyridiniumbromide or a pharmaceutically acceptable salt thereof; c)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(2-thien-2′-yl)-2-oxoethylpyridinium-4-thio}methyl-pyrazol-5-yl]pyridinium bromide or apharmaceutically acceptable salt thereof; d)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(3,5-dimethylpyrazol-1-yl)methyl}pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; e)1-(2-thien-2′-yl-2-oxoethyl)-3-[{3-phenylmethyl}-1-{2-pyridyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; f)1-(2-thien-2′-yl-2-oxoethyl)-3-[3{(3,5-dimethylpyrazol-1-yl)methyl-1-pyridyl}pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; g)1-[2-(cyclopropylamino)-2-oxoethyl]3-[3-{(3,5-dimethylpyrazol-1-yl)methyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; h)1-{2-(4-nitro-2-thienyl)-2-oxoethyl}-3-[3{(3,5-dimethylpyrazol-1-yl)ethyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; i)1-(2-cyclopropylamino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; j)3,5-bis-[1-(2-thien-2′-yl-2-oxoethyl)-pyridinium-3-yl]-pyrazoledibromide and pharmaceutically acceptable salts thereof or apharmaceutically acceptable salt thereof; k)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; l)1-(2-(5′-methyl-2-thienyl)-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; m)1-(2-thien-2′-yl-2-oxoethyl)3-[1-phenyl,3-{(3,5-dimethylpyrazol-1-yl)methyl)}pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; n)1-(2-phenyl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; o)1-(2-cyclopropylamino-2-oxoethyl)3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; p)1-(2-(4-benzyl-1-piperidinyl)-2-oxoethyl)3-[(3-phenoxymethyl)pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; q)1-(2-phenyl-2-oxoethyl)-3-[(3-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; r)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3,-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; s)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; t)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; u)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; v)1-(2-phenyl-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; w)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof x)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; y)1-[2-(1-adamantylamino)-2-oxoethyl]-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; z)1-(2-phenyl-2-oxoethyl)-3-[{3-(3,5-dimethylpyrazol-1-yl)methyl)}1-phenyl-pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; aa)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl)-methyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; bb)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; cc)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; dd)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; ee)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ff)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrozol-1-yl)methyl)pyrazole-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; gg)1-(2-(5-chloro-2-thienyl)-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; hh)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ii)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; jj)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; kk)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; ll)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; mm)3-[(3-phenylmethyl)pyrazol-5-yl]pyridine hydrochloride or apharmaceutically acceptable salt thereof; nn)3-[(3-phenoxymethyl)pyrazol-5-yl]pyridine hydrochloride or apharmaceutically acceptable salt thereof; oo)3-[(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridine or apharmaceutically acceptable salt thereof; pp)3-[3-(2-cyclohexyl-ethyl)-pyrazol-5-yl]pyridine or a pharmaceuticallyacceptable salt thereof; qq)1-(2-napthyl-2-oxoethyl)-3[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; rr)1-(phenylmethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium chloride or apharmaceutically acceptable salt thereof; ss)1-(2-thien-2′-yl-2-oxoethyl)-3[(3(-1-naphthyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; tt)1-(2-phenyl-2oxoethyl)-3[3(thienyl-2-yl-methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; uu)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[3(2-phenylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; vv)1-(2-(5-methyl2-thienyl)-2-oxoethyl)-3-[3-(3-phenoxypropyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ww)1-(isopropyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium bromide or apharmaceutically acceptable salt thereof; xx)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3-thiophenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; yy)1-(2-thien-2′-yl-2-oxoethyl)-3[(3-(N-methyl-indole-3-ylmethyl)pyrazol-5-yl]pyridinium chloride or a pharmaceutically acceptablesalt thereof; zz)1-(2-napthyl-2-oxo-ethyl)-3[(3-methyl)pyrazol-5-yl]pyridinium bromide ora pharmaceutically acceptable salt thereof; aaa) 1-(2-(1,4benzodioxane-6-yl-amino-2-oxoethy)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; bbb)1-(2-thien-2′-yl-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]-5bromo-pyridinium chloride or a pharmaceutically acceptable salt thereof;ccc) 1-(2-thien-2-′yl)-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]quinoliniumchloride or a pharmaceutically acceptable salt thereof and ddd)3-[(3-phenyl)pyrazol-5-yl)]quinoline or a pharmaceutically acceptablesalt thereof;
 33. (canceled)
 34. The method as claimed in claim 29, 30or 31, wherein said compound is selected from the group consisting of:a)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; b)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)oxazol-5-yl pyridiniumbromide or a pharmaceutically acceptable salt thereof; c)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(2-thien-2′-yl)-2-oxoethylpyridinium-4-thio}methyl-pyrazol-5-yl]pyridinium bromide or apharmaceutically acceptable salt thereof; d)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(3,5-dimethylpyrazol-1-yl)methyl}pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; e)1-(2-thien-2′-yl-2-oxoethyl)-3-[{3-phenylmethyl}-1-{2-pyridyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; f)1-(2-thien-2′-yl-2-oxoethyl)-3-[3{(3,5-dimethylpyrazol-1-yl)methyl-1-pyridyl}pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; g)1-[2-(cyclopropylamino)-2-oxoethyl]3-[3-{(3,5-dimethylpyrazol-1-yl)methyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; h)1-{2-(4-nitro-2-thienyl)-2-oxoethyl}-3-[3{(3,5-dimethylpyrazol-1-yl)ethyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; i)1-(2-cyclopropylamino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; j)3,5-bis-[1-(2-thien-2′-yl-2-oxoethyl)-pyridinium-3-yl]-pyrazoledibromide and pharmaceutically acceptable salts thereof or apharmaceutically acceptable salt thereof; k)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; l)1-(2-(5′-methyl-2-thienyl)-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; m)1-(2-thien-2′-yl-2-oxoethyl)3-[1-phenyl,3-{(3,5-dimethylpyrazol-1-yl)methyl)}pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; n)1-(2-phenyl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; o)1-(2-cyclopropylamino-2-oxoethyl)3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; p)1-(2-(4-benzyl-1-piperidinyl)-2-oxoethyl)3-[(3-phenoxymethyl)pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; q)1-(2-phenyl-2-oxoethyl)-3-[(3-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; r)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3,-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; s)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; t)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; u)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; v)1-(2-phenyl-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; w)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; x)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; y)1-[2-(1-adamantylamino)-2-oxoethyl]-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; z)1-(2-phenyl-2-oxoethyl)-3-[{3-(3,5-dimethylpyrazol-1-yl)-methyl)}1-phenyl-pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; aa)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl)-methyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; bb)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; cc)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; dd)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; ee)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ff)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrozol-1-yl)methyl)pyrazole-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; gg)1-(2-(5-chloro-2-thienyl)-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; hh)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ii)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; jj)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; kk)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; ll)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; mm)3-[(3-phenylmethyl)pyrazol-5-yl]pyridine hydrochloride or apharmaceutically acceptable salt thereof; nn)3-[(3-phenoxymethyl)pyrazol-5-yl]pyridine hydrochloride or apharmaceutically acceptable salt thereof; oo)3-[(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridine or apharmaceutically acceptable salt thereof; pp)3-[3-(2-cyclohexyl-ethyl)-pyrazol-5-yl]pyridine or a pharmaceuticallyacceptable salt thereof; qq)1-(2-napthyl-2-oxoethyl)-3[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; rr)1-(phenylmethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium chloride or apharmaceutically acceptable salt thereof; ss)1-(2-thien-2′-yl-2-oxoethyl)-3[(3(-1-naphthyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; tt)1-(2-phenyl-2oxoethyl)-3[3(thienyl-2-yl-methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; uu)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[3(2-phenylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; vv)1-(2-(5-methyl2-thienyl)-2-oxoethyl)-3-[3-(3-phenoxypropyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ww)1-(isopropyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium bromide or apharmaceutically acceptable salt thereof; xx)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3-thiophenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; yy)1-(2-thien-2′-yl-2-oxoethyl)-3[(3-(N-methyl-indole-3-ylmethyl)pyrazol-5-yl]pyridinium chloride or a pharmaceutically acceptablesalt thereof; zz)1-(2-napthyl-2-oxo-ethyl)-3[(3-methyl)pyrazol-5-yl]pyridinium bromide ora pharmaceutically acceptable salt thereof; aaa) 1-(2-(1,4benzodioxane-6-yl-amino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; bbb)1-(2-thien-2′-yl-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]-5bromo-pyridinium chloride or a pharmaceutically acceptable salt thereof;ccc) 1-(2-thien-2-′yl)-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]quinoliniumchloride or a pharmaceutically acceptable salt thereof and ddd)3-[(3-phenyl)pyrazol-5-yl)]quinoline or a pharmaceutically acceptablesalt thereof;
 35. A method of scavenging free radical in the body cellscomprising administering to a mammal in need of scavenging free radicalfrom its body cells an effective amount of a compound of general formula(I) as defined in claim 1, either singly or in combination in otherantioxidants in a pharmaceutically acceptable carrier, diluent orexcipient.
 36. The method as claimed in claim 35, wherein said compoundis selected from the group consisting of; a)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; b)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)oxazol-5-yl pyridiniumbromide or a pharmaceutically acceptable salt thereof; c)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(2-thien-2′-yl)-2-oxoethylpyridinium-4-thio}methyl-pyrazol-5-yl]pyridinium bromide or apharmaceutically acceptable salt thereof; d)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(3,5-dimethylpyrazol-1-yl)methyl}pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; e)1-(2-thien-2′-yl-2-oxoethyl)-3-[{3-phenylmethyl}-1-{2-pyridyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; f)1-(2-thien-2′-yl-2-oxoethyl)-3-[3{(3,5-dimethylpyrazol-1-yl)methyl-1-pyridyl}pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; g)1-[2-(cyclopropylamino)-2-oxoethyl]3-[3-{(3,5-dimethylpyrazol-1-yl)methyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; h)1-{2-(4-nitro-2-thienyl)-2-oxoethyl}-3-[3{(3,5-dimethylpyrazol-1-yl)ethyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; i)1-(2-cyclopropylamino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; j)3,5-bis-[1-(2-thien-2′-yl-2-oxoethyl)-pyridinium-3-yl]-pyrazoledibromide and pharmaceutically acceptable salts thereof or apharmaceutically acceptable salt thereof; k)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; l)1-(2-(5′-methyl-2-thienyl)-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; m)1-(2-thien-2′-yl-2-oxoethyl)3-[1-phenyl,3-{(3,5-dimethylpyrazol-1-yl)methyl)}pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; n)1-(2-phenyl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; o)1-(2-cyclopropylamino-2-oxoethyl)3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; p)1-(2-(4-benzyl-1-piperidinyl)-2-oxoethyl)3-[(3-phenoxymethyl)pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; q)1-(2-phenyl-2-oxoethyl)-3-[(3-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; r)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3,-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; s)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; t)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; u)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; v)1-(2-phenyl-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; w)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; x)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; y)1-[2-(1-adamantylamino)-2-oxoethyl]-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; z)1-(2-phenyl-2-oxoethyl)-3-[{3-(3,5-dimethylpyrazol-1-yl)methyl)}1-phenyl-pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; aa)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl)-methyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; bb)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; cc)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; dd)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; ee)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ff)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethyl)-1-yl)methyl)pyrazole-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; gg)1-(2-(5-chloro-2-thienyl)-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; hh)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ii)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; jj)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; kk)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; ll)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; mm)3-[(3-phenylmethyl)pyrazol-5-yl]pyridine hydrochloride or apharmaceutically acceptable salt thereof; nn)3-[(3-phenoxymethyl)pyrazol-5-yl]pyridine hydrochloride or apharmaceutically acceptable salt thereof; oo)3-[(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridine or apharmaceutically acceptable salt thereof; pp)3-[3-(2-cyclohexyl-ethyl)-pyrazol-5-yl]pyridine or a pharmaceuticallyacceptable salt thereof; qq)1-(2-napthyl-2-oxoethyl)-3[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; rr)1-(phenylmethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium chloride or apharmaceutically acceptable salt thereof; ss)1-(2-thien-2′-yl-2-oxoethyl)-3[(3(-1-naphthyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; tt)1-(2-phenyl-2oxoethyl)-3[3(thienyl-2-yl-methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; uu)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[3(2-phenylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; vv)1-(2-(5-methyl2-thienyl)-2-oxoethyl)-3-[3-(3-phenoxypropyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ww)1-(isopropyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium bromide or apharmaceutically acceptable salt thereof; xx)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3-thiophenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; yy)1-(2-thien-2′-yl-2-oxoethyl)-3[(3-(N-methyl-indole-3-ylmethyl)pyrazol-5-yl]pyridinium chloride or a pharmaceutically acceptablesalt thereof; zz)1-(2-napthyl-2-oxo-ethyl)-3[(3-methyl)pyrazol-5-yl]pyridinium bromide ora pharmaceutically acceptable salt thereof; aaa) 1-(2-(1,4benzodioxane-6-yl-amino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; bbb)1-(2-thien-2′-yl-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]-5bromo-pyridinium chloride or a pharmaceutically acceptable salt thereof;ccc) 1-(2-thien-2-′yl)-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]quinoliniumchloride or a pharmaceutically acceptable salt thereof and ddd)3-[(3-phenyl)pyrazol-5-yl)]quinoline or a pharmaceutically acceptablesalt thereof;
 37. A method of treating diseases caused by accumulationof free radicals in the body cells of a mammal comprising treating amammal affected by such disease with an effective amount of a compoundof formula (I) as defined in claim
 1. 38. The method as claimed in claim37 wherein said compound is selected from the group consisting of: a)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; b)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenylmethyl)oxazol-5-yl pyridiniumbromide or a pharmaceutically acceptable salt thereof; c)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(2-thien-2′-yl)-2-oxoethylpyridinium-4-thio}methyl-pyrazol-5-yl]pyridinium bromide or apharmaceutically acceptable salt thereof; d)1-(2-thien-2′-yl-2-oxoethyl)-3-[3-{1-(3,5-dimethylpyrazol-1-yl)methyl}pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; e)1-(2-thien-2′-yl-2-oxoethyl)-3-[{3-phenylmethyl}-1-{2-pyridyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; f)1-(2-thien-2′-yl-2-oxoethyl)-3-[3{(3,5-dimethylpyrazol-1-yl)methyl-1-pyridyl}pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; g)1-[2-(cyclopropylamino)-2-oxoethyl]3-[3-{(3,5-dimethylpyrazol-1-yl)methyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; h)1-{2-(4-nitro-2-thienyl)-2-oxoethyl}-3-[3{(3,5-dimethylpyrazol-1-yl)ethyl}-pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; i)1-(2-cyclopropylamino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; j)3,5-bis-[1-(2-thien-2′-yl-2-oxoethyl)-pyridinium-3-yl]-pyrazoledibromide and pharmaceutically acceptable salts thereof or apharmaceutically acceptable salt thereof; k)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; l)1-(2-(5′-methyl-2-thienyl)-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; m)1-(2-thien-2′-yl-2-oxoethyl)3-[1-phenyl,3-{(3,5-dimethylpyrazol-1-yl)methyl)}pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; n)1-(2-phenyl-2-oxoethyl)-3-[(3-phenylmethyl)pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; o)1-(2-cyclopropylamino-2-oxoethyl)3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; p)1-(2-(4-benzyl-1-piperidinyl)-2-oxoethyl)3-[(3-phenoxymethyl)pyrazol-5-yl]-pyridiniumbromide or a pharmaceutically acceptable salt thereof; q)1-(2-phenyl-2-oxoethyl)-3-[(3-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]-pyridiniumchloride or a pharmaceutically acceptable salt thereof; r)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3,-(3,5-dimethylpyrazol-1-yl)methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; s)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; t)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; u)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; v)1-(2-phenyl-2-oxoethyl)-3-[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; w)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; x)1-(2-thien-2′-yl-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; y)1-[2-(1-adamantylamino)-2-oxoethyl]-3-[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; z)1-(2-phenyl-2-oxoethyl)-3-[{3-(3,5-dimethylpyrazol-1-yl)methyl)}1-phenyl-pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; aa)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl)-methyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; bb)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3[(3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; cc)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; dd)1-(2-(4-nitro-2-thienyl)-2-oxoethyl)-3-[(1-phenyl-3-phenylmethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; ee)1-(2-cyclopropylamino-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ff)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethyl)-1-yl)methyl)pyrazole-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; gg)1-(2-(5-chloro-2-thienyl)-2-oxoethyl)-3-[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; hh)1-(2-phenyl-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ii)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; jj)1-(2-cyclopropylamino-2-oxoethyl)-3-[(1-phenyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; kk)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-phenyl-3-(2-cyclohexylethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; ll)1-(2-thien-2′-yl-2-oxoethyl)-3-[(1-cyclohexyl-3-phenoxymethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; mm)3-[(3-phenylmethyl)pyrazol-5-yl]pyridine hydrochloride or apharmaceutically acceptable salt thereof; nn)3-[(3-phenoxymethyl)pyrazol-5-yl]pyridine hydrochloride or apharmaceutically acceptable salt thereof; oo)3-[(3,5-dimethylpyrazol-1-yl-methyl)pyrazol-5-yl]pyridine or apharmaceutically acceptable salt thereof; pp)3-[3-(2-cyclohexyl-ethyl)-pyrazol-5-yl]pyridine or a pharmaceuticallyacceptable salt thereof; qq)1-(2-napthyl-2-oxoethyl)-3[(3-phenoxymethyl)pyrazol-5-yl]pyridiniumbromide or a pharmaceutically acceptable salt thereof; rr)1-(phenylmethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium chloride or apharmaceutically acceptable salt thereof; ss)1-(2-thien-2′-yl-2-oxoethyl)-3[(3(-1-naphthyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; tt)1-(2-phenyl-2oxoethyl)-3[3(thienyl-2-yl-methyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; uu)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[3(2-phenylethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; vv)1-(2-(5-methyl2-thienyl)-2-oxoethyl)-3-[3-(3-phenoxypropyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; ww)1-(isopropyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridinium bromide or apharmaceutically acceptable salt thereof; xx)1-(2-(5-methyl-2-thienyl)-2-oxoethyl)-3-[(3-thiophenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; yy)1-(2-thien-2′-yl-2-oxoethyl)-3[(3-(N-methyl-indole-3-ylmethyl)pyrazol-5-yl]pyridinium chloride or a pharmaceutically acceptablesalt thereof; zz)1-(2-napthyl-2-oxo-ethyl)-3[(3-methyl)pyrazol-5-yl]pyridinium bromide ora pharmaceutically acceptable salt thereof; aaa) 1-(2-(1,4benzodioxane-6-yl-amino-2-oxoethyl)-3[(3-phenylmethyl)pyrazol-5-yl]pyridiniumchloride or a pharmaceutically acceptable salt thereof; bbb)1-(2-thien-2′-yl-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]-5bromo-pyridinium chloride or a pharmaceutically acceptable salt thereof;ccc) 1-(2-thien-2-′yl)-2-oxoethyl)-3[(3-phenyl)pyrazol-5-yl]quinoliniumchloride or a pharmaceutically acceptable salt thereof and ddd)3-[(3-phenyl)pyrazol-5-yl)]quinoline or a pharmaceutically acceptablesalt thereof;
 39. The method as claimed in claim 37, wherein thediseases caused to be treated are selected from the group consisting of:a) Neurodegenerative disorders, b) Diabetes and Diabetic VascularDisorders, c) Intestinal Diseases, d) Liver Diseases, e) Cancers, f)Cardiac Diseases, g) Opthalmic Disorders, h) HIV Disease, i) RespiratoryDisease and j) Renal Diseases 40-65. (canceled)
 66. Use of a compound asdefined in claim 1 in the preparation of a dialysis fluid useful forperitoneal dialysis of a diabetic patient.